Immunomodulator and anti-inflammatory compounds

ABSTRACT

The present invention provides dihydroorotate dehydrogenase inhibitors, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of diseases or disorders wherein the inhibition of Dihydroorotate dehydrogenase is known to show beneficial effect.

This application is a continuation of U.S. patent application Ser. No.13/101,921, filed May 5, 2011, which claims the benefit of IndianProvisional Patent Application No. 1265/CHE/2010 dated 6^(th) May 2010,each of which is hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention provides dihydroorotate dehydrogenase inhibitors,methods of preparing them, pharmaceutical compositions containing themand methods of treatment, prevention and/or amelioration of diseases ordisorders wherein the inhibition of Dihydroorotate dehydrogenase isknown to show beneficial effect.

BACKGROUND OF THE INVENTION

In the recent past immense research has been dedicated to the discoveryand understanding of the structure and functions of enzymes andbio-molecules associated with various diseases. One such important classof enzymes that has been the subject of extensive research isdihydroorotate dehydrogenase (DHODH).

DHODH is an enzyme that catalyzes the fourth step in the de novobiosynthesis of pyrimidine. It converts dihydroorotate (DHO) to orotate(ORO). Human DHODH is a ubiquitous flavine mononucleotide (FMN) moietyflavoprotein. In bacteria (gene pyrD), it is located on the inner sideof the cytosolic membrane. In some yeasts, such as in Saccharomycescerevisiae (gene URA1), it is a cytosolic protein while in othereukaryotes it is found in the mitochondria (see Proc. Natl. Acad. Sci.U.S.A., 89 (19), 8966-8970).

DHODH has been classified as a family of class I or class II proteins onthe basis of the cofactor. Human DHODH belongs to the family class 2that utilizes flavine as a redox cofactor, unlike the bacterial familyclass 1 protein that uses fumarate or NAD+ instead. In the cell themammalian protein is anchored at the inner mitochondrial leaflet. There,DHODH catalyzes the conversion of DHO to ORO, which represents the ratelimiting step in the de novo pyrimidine biosynthesis. (see McLean etal., Biochemistry 2001, 40, 2194-2200). Kinetic studies indicate asequential ping-pong mechanism for the conversion of DHO to ORO (seeKnecht et al., Chem. Biol. Interact. 2000, 124, 61-76). The firsthalf-reaction comprises the reduction of DHO to ORO. Electrons aretransferred to the FMN which becomes oxidized to dihydroflavinmononucleotide (FMNH2). After dissociation of ORO from the enzyme, FMNH2is regenerated by a ubiquinone molecule, which is recruited from theinner mitochondrial membrane. Kinetic and structural studies revealedtwo distinct binding sites for DHO/ORO and ubiquinone, respectively.

Human DHODH is composed of two domains, a large C-terminal domain(Met78-Arg396) and a smaller N-terminal domain (Met30-Leu68), connectedby an extended loop. The large C-terminal domain can be best describedas an α/β-barrel fold with a central barrel of eight parallel β strandssurrounded by eight α helices. The redox site, formed by the substratebinding pocket and the site that binds the cofactor FMN, is located onthis large C-terminal domain. The small N-terminal domain, on the otherhand, consists of two α helices (labeled α1 and α2), both connected by ashort loop. This small N-terminal domain harbors the binding site forthe cofactor ubiquinone. The helices α1 and α2 span a slot of about10×20 Å² in the so-called hydrophobic patch, with the short α1-α2 loopat the narrow end of that slot. The slot forms the entrance to a tunnelthat ends at the FMN cavity nearby the α1-α2 loop. This tunnel narrowstoward the proximal redox site and ends with several charged or polarside chains (Gln47, Tyr356, Thr360, and Arg136). Structural clues, asdiscussed above, along with kinetic studies suggest that ubiquinone,which can easily diffuse into the mitochondrial inner membrane, usesthis tunnel to approach the FMN cofactor for the redox reaction (seeBaumgartner et al., J. Med. Chem. 2006, 49, 1239-1247).

A study disclosed in The Journal of Biological Chemistry 2005, 280(23),21847-21853; formally demonstrates the possibility to identify potentinhibitors of P. falciparum DHODH that do not inhibit the human enzyme.Comparison of the human DHODH crystal structures with the malaria DHODHamino acid sequence further suggests there are opportunities forspecies-specific inhibitor binding.

In the body, DHODH catalyzes the synthesis of pyrimidines, which arenecessary for cell growth. An inhibition of DHODH inhibits the growth of(pathologically) fast proliferating cells, whereas cells which grow atnormal speed may obtain their required pyrimidine bases from the normalmetabolic cycle. The most important types of cells for the immuneresponse, the lymphocytes, use exclusively the synthesis of pyrimidinesfor their growth and react particularly sensitively to DHODH inhibition.

DHODH inhibition results in decreased cellular levels of ribonucleotideuridine monophosphate (rUMP), thus arresting proliferating cells in theGl phase of the cell cycle. The inhibition of de novo pyrimidinenucleotide synthesis is of great interest in view of the observationsthat lymphocytes seem not to be able to undergo clonal expansion whenthis pathway is blocked. Substances that inhibit the growth oflymphocytes are important medicaments for the treatment of auto-immunediseases.

During homeostatic proliferation, the salvage pathway which isindependent of DHODH seems sufficient for the cellular supply withpyrimidine bases. Only, cells with a high turnover and particularly Tand B lymphocytes need the de novo pathway to proliferate. In thesecells, DHODH inhibition stops the cell cycle progression suppressing DNAsynthesis and consequently cell proliferation (see Breedveld et al., AnnRheum Dis 2000).

Therefore, inhibitors of DHODH show beneficial immunosuppressant andantiproliferative effects in human diseases characterized by abnormaland uncontrollable cell proliferation causing chronic inflammation andtissue destruction. The human enzyme dihydroorotate dehydrogenase(DHODH) represents a well-characterized target for small molecularweight Disease Modifying Antirheumatic Drugs (DMARDs).

A list of known DHODH inhibitors includes Leflunomide, Teriflunomide,Brequinar (NSC 368390) (Cancer Research 1992, 52, 3521-3527),Dichloroallyl lawsone (The Journal of Biological Chemistry 1986,261(32), 14891-14895), Maritimus (FK 778) (Drugs of the Future 2002,27(8), 733-739) and Redoxal (The Journal of Biological Chemistry 2002,277(44), 41827-41834),

Leflunomide, teriflunomide, and brequinar have been studiedsignificantly.

In general, inhibitors of DHODH show beneficial immunosuppressive andantiproliferative activities, most pronounced on T-cells (see Fairbankset al., J. Biol. Chem. 1995, 270, 29682-29689). Brequinar andleflunomide are two examples of small molecular weight inhibitors ofDHODH that had been in clinical development. The latter is used in thetreatment of rheumatoid arthritis refractive to methotrexate (see RozmanJ. Rheumatol Suppl. 1998, 53, 27-31; Pally et al., Toxicology 1998, 127,207-222). Clinical application of both molecules suffers from variousside effects. On the basis of very good efficacy in animal models,brequinar was originally developed for the therapy of organ transplantrejection but was switched to cancer as a secondary indication. Thecompound failed in the clinic due to its narrow therapeutic window. Oraladministration of brequinar and some of its analogues resulted in toxiceffects, including leukocytopenia and thrombocytopenia, when given incombination with cyclosporine. The application of leflunomide might beflawed by its long half-life time of approximately 2 weeks whichrepresents a serious obstacle in patients that have developed sideeffects (see Fox et al. J. Rheumatol Suppl. 1998, 53, 20-26; Alldred etal., Expert Opin. Pharmacother. 2001, 2, 125-137).

In addition to abolish lymphocyte proliferation, inhibitors of DHODH(e.g., teriflunomide, maritimus (FK778) and brequinar) have ananti-inflammatory action by inhibition of cytokine production andnuclear factor (NF)-kB-signalling, monocyte migration and increasedproduction of transforming growth factor beta-1 and induce a shift fromT helper cell type 1 (TM) to type 2 (Th2) subpopulation differentiation(Manna et al., J. Immunol. 2000; Dimitrova et al., J. Immunol. 2002).Furthermore, the osteoclast differentiation mediated by ReceptorActivator for Nuclear Factor k B Ligand (RANKL) decreased by DHODHinhibition (Urushibara et al., Arthrititis Rheum 2004). Inco-crystallisation experiments with two inhibitors of DHODH that reachedclinical trials, brequinar (Dexter et al., Cancer Res. 1985) andteriflunomide (A77-1726), were both found to bind in a common site, thatis also believed to be the binding site of the cofactor ubiquinone (Liuet al., Struc. Fold. Des. 2000).

Leflunomide sold under the trade name Arava (EP 0 780 128, WO 97/34600),was the first DHODH inhibitor that reached the market place. Leflunomideis the prodrug of teriflunomide, which is the active metaboliteinhibiting human DHODH with a moderate potency (Fox et al., J.Rheumatol. Suppl. 1998).

Leflunomide is a DMARD from Aventis, which was approved by the FDA forthe treatment of rheumatoid arthritis in 1998 and by the EMEA for thetreatment of psoriatic arthritis in 2004. Currently leflunomide is underactive development for the treatment of systemic lupus erythematosus,Wegener's granulomatosis (Metzler et al., Rheumatology 2004, 43(3),315-320) and HIV infection. Moreover, teriflunomide, its activemetabolite is efficacious in multiple sclerosis and is currently inPhase III clinical trials (O'Connor et al., Neurology 2006).

Other data are emerging in other closely related diseases such asankylosing spondilitis (Haibel et al., Ann. Rheum. Dis. 2005),polyarticular juvenile idiopathic arthritis (Silverman et al., ArthritisRheum. 2005) and Sarcoidosis (Baughman et al., Sarcoidosis Vase. DiffuseLung Dis. 2004). Furthermore, leflunomide and FK778 have shown antiviralactivity against cytomegalovirus. Leflunomide is currently indicated assecond-line therapy for cytomegalovirus disease after organtransplantation (John et al., Transplantation 2004). In additionleflunomide reduces HIV replication by about 75% at a concentration thatcan be obtained with conventional dosing (Schlapfer et al., AIDS 2003).

DHODH inhibitors under investigation at various stages of clinicaltrials are 4SC-101 (Phase-II) from 4SC AG; LAS-186323 (Phase-I) fromAlmirall Laboratories SA and ABR-224050, ABR-222417, & ABR-214658(Preclinical) from Active Biotech AB. The exact structures of all thesemolecules have not yet been disclosed.

Various DHODH inhibitors have been disclosed for the treatment orprevention of autoimmune diseases, immune and inflammatory diseases,destructive bone disorders, malignant neoplastic diseases,angiogenic-related disorders, viral diseases, and infectious diseases.See for example WO2009137081; WO2009133379; WO 2009021696; WO2009082691;WO2009029473; WO2009153043; US2009209557; US2009 062318; US2009082374;WO2008097180; WO2008077639; US2008027079; US2007 299114; US2007027193;US2007224672; WO2007149211; JP2007015952; WO2006 044741; WO2006001961;WO2006051937; WO2006038606; WO2006022442; US2006 199856; WO2005075410;U.S. Pat. No. 7,074,831; WO2004056797; U.S. Pat. No. 7,247,736;WO2004056747; WO 2004056746; JP2004099586; WO2003097574; WO2003030905;WO2003006425; WO2003 006424; US2003203951; WO2002080897; U.S. Pat. No.7,176,241; U.S. Pat. No. 7,423,057; WO2001024785; U.S. Pat. No.6,841,561; WO9945926; WO9938846; WO9941239; EP767167 and U.S. Pat. No.5,976,848.

For additional reviews and literature regarding DHODH inhibitors see Bio& Med. Chem. Letters, 20(6), 2010, Pages 1981-1984; J. Med. Chem. 2009,52, 2683-2693; J. Med. Chem. 2008, 51 (12), 3649-3653. All of thesepatents, patent applications, and literature disclosures areincorporated herein as reference in their entirety for all purposes.

Despite the progress made in the area of DHODH inhibition in humandiseases, challenges remain in terms of the side effects and desiredclinical benefits from small molecule inhibitors. Accordingly, therestill remains an unmet and dire need for small molecule DHODH inhibitorsfor the treatment and/or amelioration of diseases and disorders known tobe associated with DHODH.

SUMMARY OF THE INVENTION

The present invention relates to compounds of formula (I), methods fortheir preparation, pharmaceutical compositions containing them andmethods of use with them. The compound of formula (I) has the structure:

or a tautomer, stereoisomer (such as an enantiomer or diastereomer),pharmaceutically acceptable salt, pharmaceutically acceptable ester,prodrug or N-oxide thereof, whereinRing A is independently selected from a substituted or unsubstitutedmonocyclic aryl and a substituted or unsubstituted monocyclicheteroaryl, wherein each occurrence of X is independently CR⁴ or N;Ring B is independently selected from a substituted or unsubstitutedmonocyclic aryl and a substituted or unsubstituted monocyclicheteroaryl, wherein each occurrence of X¹ is independently CR⁴ or N;R is hydrogen, substituted or unsubstituted (C₁₋₆)alkyl or —OR^(a);R¹ is selected from —OH, —NR^(a)OH, —COOH, —COOR^(a), —CR^(a)R^(b)OH,—CR^(a)R^(b)COOH, —SO₂R^(a), —CR^(a)R^(b)SO₂R^(a), —SO₃R^(a),—CR^(a)R^(b)—SO₃R^(a), —C(═Y)—NR^(a)R^(b) and —S(═O)_(q)—NR^(a)R^(b) oran isostere of —COOH group, such as SO₃H, CONHOH, B(OH)₂, PO₃R^(a)R^(b),SO₂NR^(a)R^(b), a tetrazole, an amide, an ester or an acid anhydride oroptionally represent halogen, substituted or unsubstituted (C₁₋₆)alkylor Cy¹;X² is N or CR² and X³ is N or CR³, wherein R² and R³ may be same ordifferent and are independently selected from hydrogen, halogen,substituted or unsubstituted (C₁₋₆)alkyl or substituted or unsubstituted(C₁₋₆)alkoxy.L¹ and L² are independently absent or selected from —(CR^(a)R^(b))_(n)—,—O—, —S(═O)_(q)—, —NR^(a)—, —C(═Y)—, —C(═Y)—CR^(a)R^(b),—CR^(a)R^(b)—C(═Y)—, —C(═Y)—C(═Y)—, —CR^(a)R^(b)—Y—,—C(═Y)—NR^(a)R^(b)—, —S(═O)_(q)—NR^(a)R^(b)—, —NR^(a)R^(b)—C(═Y)—,—NR^(a)R^(b)—S(═O)_(q)—, substituted or unsubstituted (C₁₋₂)alkyl,substituted or unsubstituted (C₂)alkenyl, and substituted orunsubstituted (C₂)alkynyl; optionally each of substituted orunsubstituted (C₁₋₂)alkyl, substituted or unsubstituted (C₂)alkenyl, andsubstituted or unsubstituted (C₂)alkynyl may be interrupted with —O—,—C(═Y)—, —S(═O)_(q)— and —NR^(a)—;Cy is selected from substituted or unsubstituted cycloalkyl, substitutedor unsubstituted heterocyclic group, substituted or unsubstituted aryland substituted or unsubstituted heteroaryl;Cy¹ is selected from substituted or unsubstituted monocyclic cycloalkyl,substituted or unsubstituted monocyclic heterocyclic group, substitutedor unsubstituted monocyclic aryl and substituted or unsubstitutedmonocyclic heteroaryl;R⁴ is independently selected hydrogen, hydroxy, halogen, cyano, —OR^(a),—S(═O)_(q)—R^(a), —NR^(a)R^(b), —C(═Y)—R^(a), —C(═Y)—OR^(a),—C(═Y)—NR^(a)R^(b), —S(═O)_(q)—NR^(a)R^(b), substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkylakyl, substituted orunsubstituted cycloalkenyl or when two R⁴ substituents are present, theymay be joined to a form a substituted or unsubstituted saturated orunsaturated 3-10 member ring, which may optionally include heteroatomswhich may be same or different and are selected from O, NR^(a) or S, oralternatively when two R⁴ substituent are ortho to each other on anaromatic ring may be joined to form a substituted or unsubstitutedsaturated or unsaturated 4-10 member ring, which may optionally includeone or more heteroatoms which may be same or different and are selectedfrom O, NR^(a) or S;each occurrence of R^(a) and R^(b) may be the same or different and areindependently selected from hydrogen, halogen, hydroxy, cyano,substituted or unsubstituted (C₁₋₆)alkyl, —OR^(c) (wherein R^(c) issubstituted or unsubstituted (C₁₋₆)alkyl) or when R^(a) and R^(b) aredirectly bound to a common atom, they may be joined to form an oxo group(═O) or form a substituted or unsubstituted saturated or unsaturated3-10 member ring, which may optionally include heteroatoms which may bethe same or different and are selected from O, NR^(a) or S;each occurrence of Y is independently selected from O, S and NR^(a);each occurrence of n independently represents an integer 0, 1, 2, 3, or4; andeach occurrence of q independently represents an integer 0, 1 or 2.

Some of the compounds of the present invention appear in differenttautomeric forms. For example, Ring A can include a —C(OH)═N— groupwhich interconverts to —C(O)—NH— and back to —C(OH)═N— again.

Yet another embodiment is a compound having the formula (I) wherein ringA is selected from

optionally substituted with one or more R⁴.

Yet another embodiment is a compound having the formula (I) wherein R¹is —COOH,

Yet another embodiment is a compound having the formula (I) wherein eachoccurrence of Y is O.

Yet another embodiment is a compound having the formula (I) wherein thevariable Y between ring A and the group —N(R)— is O.

Yet another embodiment is a compound having the formula (I) wherein R isH.

Yet another embodiment is a compound having the formula (I) wherein eachoccurrence of X is CH, C—Cl, or C—F.

Yet another embodiment, is a compound having the formula (I) whereineach occurrence of X¹ is CH, N or CF.

Yet another embodiment, is a compound having the formula (I) wherein X²is CH, N, CCl or CF.

Yet another embodiment, is a compound having the formula (I) wherein X³is CH, N, CCl or CF.

Yet another embodiment is a compound having the formula (I) wherein ringB is selected from

optionally substituted with one or more R⁴.

Yet another embodiment is a compound having the formula (I), wherein L₁and L₂ are absent.

Yet another embodiment is a compound having the formula (I), wherein L₁is absent and L₂ is —O—CR^(a)R^(b).

Yet another embodiment, is a compound having the formula (I), wherein Cyis selected from

each optionally substituted with one or more R⁴.

In one preferred embodiment, Ring A is phenyl, Ring B is phenyl, Cy isphenyl or 3-ethyl-1H-indol-5-yl, R¹ is —COOH, Y is O, L¹ is absent, andL² is absent. In a more preferred embodiment, Cy is phenyl substitutedwith one or more C₁-C₄ alkoxy, —S—(C₁-C₄ alkyl), and/or halogen. In amore preferred embodiment, Ring B is phenyl substituted with one or morefluoro groups.

Yet another embodiment is a compound of formula (IA)

or a tautomer, stereoisomer (such as an enantiomer or diastereomer),pharmaceutically acceptable salt, pharmaceutically acceptable ester,prodrug or N-oxide thereof, whereinRing A is selected from

optionally substituted with one or more R⁴, and R¹ is independentlyselected from —OH, —NR^(a)OH, —COOH, —COOR^(a), or an isostere of —COOHgroup, such as SO₃H, CONHOH, B(OH)₂, PO₃R^(a)R^(b), SO₂NHR^(a), atetrazole, an amide, an ester or an acid anhydride.Ring B is selected from

optionally substituted with one or more R⁴.and all other variables are the same as described above in relation toformula (I).

Yet another embodiment is a compound of formula (IA)

or a tautomer, stereoisomer (such as an enantiomer or diastereomer),pharmaceutically acceptable salt, pharmaceutically acceptable ester,prodrug or N-oxide thereof, whereinRing A is selected from

Ring B is selected from

optionally substituted with one or more R⁴;L₂ is absent or is O—CR^(a)R^(b)—;Cy is substituted phenyl, substituted indole or substituted indazole,such as

and all other variables are the same as described above in relation toformula (I).

Representative compounds of the present invention include thosespecified below and pharmaceutically acceptable salts thereof (Table 1).The present invention should not be construed to be limited to them.

-   1. 2-(3,5-Difluoro-3′-methoxybiphenyl-4-ylcarbamoyl)benzoic acid-   2. 2-(3,5-Difluoro-3′-methoxybiphenyl-4-ylcarbamoyl)benzenesulfonic    acid-   3. 2-(6-(3-Methoxyphenyl)pyridin-3-ylcarbamoyl)benzoic acid-   4. 2-(3′-Ethoxy-3-fluorobiphenyl-4-ylcarbamoyl)benzoic acid-   5. 2-(3′-Ethoxy-3,5-difluorobiphenyl-4-ylcarbamoyl)benzoic acid-   6.    3-(3,5-Difluoro-3′-methoxybiphenyl-4-ylcarbamoyl)pyrazine-2-carboxylic    acid-   7.    3-(3,5-Difluoro-3′-ethoxybiphenyl-4-ylcarbamoyl)pyrazine-2-carboxylic    acid-   8. 2-(2′-Chloro-3,5-difluorobiphenyl-4-ylcarbamoyl)benzoic acid-   9.    3-[3′-(Benzyloxy)-3,5-difluorobiphenyl-4-ylcarbamoyl]pyrazine-2-carboxylic    acid-   10. 2-(3,5-Difluorobiphenyl-4-ylcarbamoyl)benzoic acid-   11.    3-(3-Chloro-3′-ethoxy-5-fluorobiphenyl-4-ylcarbamoyl)pyrazine-2-carboxylic    acid-   12.    2-[3,5-Difluoro-3′-(trifluoromethoxy)biphenyl-4-ylcarbamoyl]benzoic    acid-   13. 2-[3′-(Benzyloxy)-3,5-difluorobiphenyl-4-ylcarbamoyl]benzoic    acid-   14.    4,5-Dichloro-2-(3-chloro-3′-ethoxy-5-fluorobiphenyl-4-ylcarbamoyl)benzoic    acid-   15. 2-(3-Chloro-3′-ethoxy-5-fluorobiphenyl-4-ylcarbamoyl)benzoic    acid-   16.    4,5-Dichloro-2-(3,5-difluoro-3′-methoxybiphenyl-4-ylcarbamoyl)benzoic    acid-   17.    4,5-Dichloro-2-(3′-ethoxy-3,5-difluorobiphenyl-4-ylcarbamoyl)benzoic    acid-   18. 2-(3,5-Dichloro-3′-methoxybiphenyl-4-ylcarbamoyl)benzoic acid-   19. 2-(3-Chloro-5-fluoro-3′-propoxybiphenyl-4-ylcarbamoyl)benzoic    acid-   20. 2-(3-Chloro-2′,5-difluorobiphenyl-4-ylcarbamoyl)benzoic acid-   21. 2-(3,5-Dichloro-3′-ethoxybiphenyl-4-ylcarbamoyl)benzoic acid-   22. 2-[3-Fluoro-3′-(trifluoromethoxy)biphenyl-4-ylcarbamoyl]benzoic    acid-   23. 2-[2′-Fluoro-3-(trifluoromethoxy)biphenyl-4-ylcarbamoyl]benzoic    acid-   24. 2-(3,5-Dichloro-2′-fluorobiphenyl-4-ylcarbamoyl)benzoic acid-   25. 2-(3,5-Difluoro-3′-isopropoxybiphenyl-4-ylcarbamoyl)benzoic acid-   26. 2-(3,5-Difluoro-3′-propoxybiphenyl-4-ylcarbamoyl)benzoic acid-   27.    4,5-Dichloro-2-(2′,3-dichloro-5-fluorobiphenyl-4-ylcarbamoyl)benzoic    acid-   28.    3,6-dichloro-2-(3′-ethoxy-3,5-difluorobiphenyl-4-ylcarbamoyl)benzoic    acid-   29. 2-(3′-butoxy-3-chloro-5-fluorobiphenyl-4-ylcarbamoyl)benzoic    acid-   30.    4,5-Dichloro-2-(2′-chloro-3,5-difluorobiphenyl-4-ylcarbamoyl)benzoic    acid-   31. 2-(3-Chloro-5-fluoro-3′-isobutoxybiphenyl-4-ylcarbamoyl)benzoic    acid-   32. 2-(2′,3,5-Trifluorobiphenyl-4-ylcarbamoyl)benzoic acid-   33. 2-(2′,3,5-Trichlorobiphenyl-4-ylcarbamoyl)benzoic acid-   34. 2-(3,5-Difluoro-3′-isobutoxybiphenyl-4-ylcarbamoyl)benzoic acid-   35. 2-(3′-Butoxy-3,5-difluorobiphenyl-4-ylcarbamoyl)benzoic acid-   36.    N-(3-Chloro-3′-ethoxy-5-fluorobiphenyl-4-yl)-2-(hydroxymethyl)benzamide-   37.    N-(3′-Ethoxy-3,5-difluorobiphenyl-4-yl)-2-(hydroxymethyl)benzamide-   38.    2-(3-Chloro-3′-ethoxy-5-fluorobiphenyl-4-ylcarbamoyl)-6-fluorobenzoic    acid-   39.    2-[3-Chloro-5-fluoro-3′-(trifluoromethoxy)biphenyl-4-ylcarbamoyl]benzoic    acid-   40. 2-[4-(Benzyloxy)-2,6-difluorophenylcarbamoyl]benzoic acid-   41.    2-[3′-(Cyclopentyloxy)-3,5-difluorobiphenyl-4-ylcarbamoyl]benzoic    acid-   42.    2-(3-Chloro-3′-(cyclopentyloxy)-5-fluorobiphenyl-4-ylcarbamoyl)benzoic    acid-   43.    2-[3′-(Difluoromethoxy)-3,5-difluorobiphenyl-4-ylcarbamoyl]benzoic    acid-   44.    2-[3-Chloro-3′-(difluoromethoxy)-5-fluorobiphenyl-4-ylcarbamoyl]benzoic    acid-   45.    2-(2′-Chloro-3,5-difluoro-5′-methoxybiphenyl-4-ylcarbamoyl)benzoic    acid-   46. 2-(3,3′,5-Trifluoro-5′-methoxybiphenyl-4-ylcarbamoyl)benzoic    acid-   47.    2-[4-(Benzo[d][1,3]dioxol-5-yl)-2,6-difluorophenylcarbamoyl]benzoic    acid-   48.    2-[4-(Benzo[d][1,3]dioxol-5-yl)-2-chloro-6-fluorophenylcarbamoyl]benzoic    acid-   49. 2-(3,5-Difluoro-3′,4′-dimethoxybiphenyl-4-ylcarbamoyl)benzoic    acid-   50. 2-(3,3′,5-Trifluoro-5′-methoxybiphenyl-4-ylcarbamoyl)benzoic    acid-   51.    2-(3,3′-Dichloro-5-fluoro-5′-methoxybiphenyl-4-ylcarbamoyl)benzoic    acid-   52.    2-[4-(2,3-Dihydrobenzofuran-5-yl)-2,6-difluorophenylcarbamoyl]benzoic    acid-   53.    2-[2-Chloro-4-(2,3-dihydrobenzofuran-5-yl)-6-fluorophenylcarbamoyl]benzoic    acid-   54.    2-[4-(1,3-Dimethyl-1H-indazol-5-yl)-2,6-difluorophenylcarbamoyl]benzoic    acid-   55.    2-(3′-Chloro-3,5-difluoro-5′-methoxybiphenyl-4-ylcarbamoyl)benzoic    acid-   56.    2-(3-Chloro-5-fluoro-3′,4′-dimethoxybiphenyl-4-ylcarbamoyl)benzoic    acid-   57.    2-(2′,3-Dichloro-5-fluoro-5′-methoxybiphenyl-4-ylcarbamoyl)benzoic    acid-   58. 2-(2′,3,5-Trifluoro-5′-methoxybiphenyl-4-ylcarbamoyl)benzoic    acid-   59.    2-(4′-Chloro-3,5-difluoro-3′-methoxybiphenyl-4-ylcarbamoyl)benzoic    acid-   60.    2-(3,4′-Dichloro-5-fluoro-3′-methoxybiphenyl-4-ylcarbamoyl)benzoic    acid-   61.    2-(3-chloro-2′,5-difluoro-5′-methoxybiphenyl-4-ylcarbamoyl)benzoic    acid-   62. 2-(3,4′,5-trifluoro-3′-methoxybiphenyl-4-ylcarbamoyl)benzoic    acid-   63.    2-[2,6-difluoro-4-(3-methyl-1H-indol-5-yl)phenylcarbamoyl]benzoic    acid-   64.    2-[2,6-difluoro-4-(3-methyl-1H-indazol-5-yl)phenylcarbamoyl]benzoic    acid-   65. 2-(3-chloro-3′-ethyl-5-fluorobiphenyl-4-ylcarbamoyl)benzoic acid-   66.    2-(3-chloro-3′-ethoxy-2′,5-difluorobiphenyl-4-ylcarbamoyl)benzoic    acid-   67.    2-[2-chloro-4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-fluorophenylcarbamoyl]benzoic    acid-   68.    2-[3-chloro-5-fluoro-3′-(2,2,2-trifluoroethoxy)biphenyl-4-ylcarbamoyl]benzoic    acid-   69. 2-(3-fluoro-3′-methoxybiphenyl-4-ylcarbamoyl)benzoic acid-   70. 2-(3′-ethoxybiphenyl-4-ylcarbamoyl)benzoic acid-   71. 2-[3′-(ethylthio)-3,5-difluorobiphenyl-4-ylcarbamoyl]benzoic    acid-   72. 2-[3′-(ethylsulfinyl)-3,5-difluorobiphenyl-4-ylcarbamoyl]benzoic    acid-   73. 2-(3′-cyclopropoxy-3,5-difluorobiphenyl-4-ylcarbamoyl)benzoic    acid-   74.    2-(3′-ethoxy-3,5-difluorobiphenyl-4-ylcarbamoyl)-6(5)-methylbenzoic    acid-   75. 2-[4-(3-ethyl-1H-indol-5-yl)-2,6-difluorophenylcarbamoyl]benzoic    acid-   76. 2-(3′-ethoxy-3,5-difluorobiphenyl-4-ylcarbamoyl)nicotinic acid-   77. 4-(3′-ethoxy-3,5-difluorobiphenyl-4-ylcarbamoyl)nicotinic acid-   78.    2-[3′-(ethylthio)-2,3,5,6-tetrafluorobiphenyl-4-ylcarbamoyl]benzoic    acid-   79. 2-(2′-chloro-2-fluoro-5′-methoxybiphenyl-4-ylcarbamoyl)benzoic    acid-   80. 2-(3-fluoro-3′-propoxybiphenyl-4-ylcarbamoyl)benzoic acid-   81. 2-(3′-propoxybiphenyl-4-ylcarbamoyl)benzoic acid-   82. 2-[3′-(ethylthio)-2-fluorobiphenyl-4-ylcarbamoyl]benzoic acid-   83.    2-[3,5-difluoro-3′-(2,2,2-trifluoroethoxy)biphenyl-4-ylcarbamoyl]benzoic    acid-   84. 2-(3′-ethyl-3,5-difluorobiphenyl-4-ylcarbamoyl)benzoic acid-   85. 2-(biphenyl-4-ylcarbamoyl)benzoic acid-   86. 2-(2′-chlorobiphenyl-4-ylcarbamoyl)benzoic acid-   87. 2-(3′-methoxybiphenyl-4-ylcarbamoyl)benzoic acid-   88. 2-[3′-(trifluoromethoxy)biphenyl-4-ylcarbamoyl]benzoic acid-   89. 2-[3′-(ethylthio)-2,6-difluorobiphenyl-4-ylcarbamoyl]benzoic    acid-   90. 2-(3′-ethylbiphenyl-4-ylcarbamoyl)benzoic acid-   91. 2-(3′-butoxy-2,3,5,6-tetrafluorobiphenyl-4-ylcarbamoyl)benzoic    acid-   92. 2-(3′-butoxy-3-fluorobiphenyl-4-ylcarbamoyl)benzoic acid-   93.    2-[3,5-difluoro-3′-(trifluoromethoxy)biphenyl-4-ylcarbamoyl]benzoic    acid-   94. 2-(3′-cyclopropoxy-3-fluorobiphenyl-4-ylcarbamoyl)benzoic acid-   95. 2-(3′-cyclopropoxybiphenyl-4-ylcarbamoyl)benzoic acid-   96. 2-(3′-butoxybiphenyl-4-ylcarbamoyl)benzoic acid-   97. 2-(3′-butoxy-2-fluorobiphenyl-4-ylcarbamoyl)benzoic acid-   98. 2-(3′-Butoxy-2,6-difluorobiphenyl-4-ylcarbamoyl)benzoic acid-   99.    2-[2,6-Difluoro-4-(3-propyl-1H-indol-5-yl)phenylcarbamoyl]benzoic    acid-   100.    2-[2-Chloro-4-(3-ethyl-1H-indol-5-yl)-6-fluorophenylcarbamoyl]benzoic    acid

TABLE 1 Ex. Structure  1.

 2.

 3.

 4.

 5.

 6.

 7.

 8.

 9.

 10.

 11.

 12.

 13.

 14.

 15.

 16.

 17.

 18.

 19.

 20.

 21.

 22.

 23.

 24.

 25.

 26.

 27.

 28.

 29.

 30.

 31.

 32.

 33.

 34.

 35.

 36.

 37.

 38.

 39.

 40.

 41.

 42.

 43.

 44.

 45.

 46.

 47.

 48.

 49.

 50.

 51.

 52.

 53.

 54.

 55.

 56.

 57.

 58.

 59.

 60.

 61.

 62.

 63.

 64.

 65.

 66.

 67.

 68.

 69.

 70.

 71.

 72.

 73.

 74.

 75.

 76.

 77.

 78.

 79.

 80.

 81.

 82.

 83.

 84.

 85.

 86.

 87.

 88.

 89.

 90.

 91.

 92.

 93.

 94.

 95.

 96.

 97.

 98.

 99.

100

Yet another embodiment is a method of inhibiting DHODH in a patient inneed thereof by administering to the patient an effective amount of acompound of formula (I) or/and (IA).

Yet another embodiment is a method of inhibiting IL-17 in a patient inneed thereof by administering to the patient an effective amount of acompound of formula (I) or/and (IA).

In particular compounds of formula (I) or/and (IA), or theirpharmaceutically acceptable salts thereof are DHODH inhibitors useful inthe treatment, prevention and/or amelioration of diseases or disorderswherein the inhibition of DHODH is known to show beneficial effect.

Another embodiment of the present invention is a method for treating animmunological disorder, inflammatory disorder, cancer or otherproliferative disease via inhibition of DHODH by administering to apatient in need of such treatment an effective amount of at least onecompound of formula (I) or/and (IA), as defined above.

Another embodiment of the present invention is a method for treating animmunological disorder, inflammatory disorder, cancer or otherproliferative disease via inhibition of IL-17 either directly or byinhibition of DHODH by administering to a patient in need of suchtreatment an effective amount of at least one compound of formula (I)or/and (IA), as defined above.

Another embodiment of the present invention is a method for treating animmunological disorder, inflammatory disorder, cancer or otherproliferative disease via inhibition of IL-17 as well DHODH byadministering to a patient in need of such treatment an effective amountof at least one compound of formula (I) or/and (IA), as defined above.

Yet another embodiment of the present invention is a method for treatingan immunological disorder, inflammatory disorder, cancer or otherproliferative disease via inhibition of DHODH by administering to apatient in need of such treatment an effective amount of at least onecompound of formula (I) or/and (IA), as defined above, in combination(simultaneously or sequentially) with at least one otheranti-inflammatory, immunomodulator or anti-cancer agent.

The compounds of formula (I) or/and (IA), are useful in the treatment ofa variety of disorders, including, but not limited to, autoimmunediseases, immune and inflammatory diseases, destructive bone disorders,cancers and malignant neoplastic diseases, angiogenic-related disorders,viral diseases, and infectious diseases. Such disorders include, but arenot limited to:

-   -   Autoimmune diseases which may be prevented (prophylactically) or        treated include but are not limited to rheumatoid arthritis,        psoriatic arthritis, systemic lupus erythematosus, multiple        sclerosis, psoriasis, ankylosing spondilytis, Wegener's        granulomatosis, polyarticular juvenile idiopathic arthritis,        inflammatory bowel disease such as ulcerative colitis and        Crohn's disease, Reiter's syndrome, fibromyalgia and type-1        diabetes.    -   Immune and inflammatory diseases which may be prevented        (prophylactically) or treated include but are not limited to        asthma, COPD, respiratory distress syndrome, acute or chronic        pancreatitis, graft versus-host disease, chronic sarcoidosis,        transplant rejection, contact dermatitis, atopic dermatitis        allergic rhinitis, allergic conjunctivitis, Behçet's syndrome,        inflammatory eye conditions such as conjunctivitis and uveitis.    -   Destructive bone disorders which may be prevented or treated        include but are not limited to osteoporosis, osteoarthritis and        multiple myeloma-related bone disorder.    -   Cancers and malignant neoplastic diseases that may be prevented        (prophylactically) or treated include but are not limited to        prostate, ovarian and brain cancer. Carcinoma, including that of        the bladder, breast, colon, kidney, liver, lung, including small        cell lung cancer, esophagus, gall bladder, ovary, pancreas,        stomach, cervix, thyroid, prostate, and skin, including squamous        cell carcinoma; hematopoietic tumors of lymphoid lineage,        including leukemia, acute lymphocytic leukemia, acute        lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma,        Hodgkin's lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma        and Burkett's lymphoma; hematopoietic tumors of myeloid lineage,        including acute and chronic myelogenous leukemias,        myelodysplastic syndrome and promyelocytic leukemia; tumors of        mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma;        tumors of the central and peripheral nervous system, including        astrocytoma, neuroblastoma, glioma and schwannomas; and other        tumors, including melanoma, seminoma, teratocarcinoma,        osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid        follicular cancer and Kaposi's sarcoma.    -   Agiogenesis-related disorders that may be prevented or treated        include but are not limited to hemangiomas, ocular        neovascularization, macular degeneration or diabetic        retinopathy.    -   Viral diseases which may be prevented or treated include but are        not limited to HIV infection, hepatitis and cytomegalovirus        infection.    -   Infectious diseases which may be prevented or treated include        but are not limited to sepsis, septic shock, endotoxic shock,        Gram negative sepsis, toxic shock syndrome, Shigellosis and        other protozoal infestations such as malaria.

The compounds of the present invention as modulators of apoptosis, areuseful in the treatment of cancer (including but not limited to thosetypes mentioned herein above), viral infections (including but notlimited to herpevirus, poxvirus, Epstein-Barr virus, Sindbis virus andadenovirus), prevention of AIDS development in HIV-infected individuals,autoimmune diseases (including but not limited to systemic lupus,erythematosus, autoimmune mediated glomerulonephritis, rheumatoidarthritis, psoriasis, inflammatory bowel disease, and autoimmunediabetes mellitus), neurodegenerative disorders (including but notlimited to Alzheimer's disease, AIDS-related dementia, Parkinson'sdisease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinalmuscular atrophy and cerebellar degeneration), myelodysplasticsyndromes, aplastic anemia, ischemic injury associated with myocardialinfarctions, stroke and reperfusion injury, arrhythmia, atherosclerosis,toxin-induced or alcohol related liver diseases, hematological diseases(including but not limited to chronic anemia and aplastic anemia),degenerative diseases of the musculoskeletal system (including but notlimited to osteoporosis and arthritis) aspirin-sensitive rhinosinusitis,cystic fibrosis, multiple sclerosis, kidney diseases and cancer pain.

The compounds of present invention can modulate the level of cellularRNA and DNA synthesis. These agents are therefore useful in thetreatment of viral infections (including but not limited to HIV, humanpapilloma virus, herpesvirus, poxvirus, Epstein-Barr virus, Sindbisvirus and adenovirus).

The compounds of the present invention are useful in the chemopreventionof cancer. Chemoprevention is defined as inhibiting the development ofinvasive cancer by either blocking the initiating mutagenic event or byblocking the progression of pre-malignant cells that have alreadysuffered an insult or inhibiting tumor relapse. The compounds are alsouseful in inhibiting tumor angiogenesis and metastasis.

The compounds of the present invention may also be combined with otheractive compounds in the treatment of diseases wherein the inhibition ofDHODH is known to show beneficial effect.

In other embodiments, the diseases, conditions or disorders that benefitfrom inhibition of DHODH include, but are not limited to, an immunesystem-related disease (e.g., an autoimmune disease), a disease ordisorder involving inflammation (e.g., asthma, chronic obstructivepulmonary disease, rheumatoid arthritis, inflammatory bowel disease,glomerulonephritis, neuroinflammatory diseases, multiple sclerosis,uveitis and disorders of the immune system), cancer or otherproliferative disease, hepatic diseases or disorders, renal diseases ordisorders.

In one embodiment, compounds described herein are used asimmunosuppresants to prevent transplant graft rejections, allogeneic orxenogeneic transplantation rejection (organ, bone marrow, stem cells,other cells and tissues), and graft-versus-host disease. In otherembodiments, transplant graft rejections result from tissue or organtransplants. In further embodiments, graft-versus-host disease resultsfrom bone marrow or stem cell transplantation.

More particularly, the compounds of formula (I) or/and (IA) are usefulin the treatment of a variety of inflammatory diseases including, butnot limited to, inflammation, glomerulonephritis, uveitis, hepaticdiseases or disorders, renal diseases or disorders, chronic obstructivepulmonary disease, rheumatoid arthritis, inflammatory bowel disease,vasculitis, dermatitis, osteoarthritis, inflammatory muscle disease,allergic rhinitis, vaginitis, interstitial cystitis, scleroderma,osteoporosis, eczema, allogeneic or xenogeneic transplantation, graftrejection, graft-versus-host disease, corneal transplant rejection,lupus erythematosus, systemic lupus erythematosus, prolipherative lupusnephritis, type I diabetes, pulmonary fibrosis, dermatomyositis,thyroiditis, myasthenia gravis, autoimmune hemolytic anemia, cysticfibrosis, chronic relapsing hepatitis, primary biliary cirrhosis,allergic conjunctivitis, hepatitis and atopic dermatitis, asthma andSjogren's syndrome.

In one embodiment, the compounds described herein are useful in thetreatment of a variety of diseases including Felty's syndrome, Wegener'sgranulomatosis, Crohn's disease, sarcoidosis, Still's disease,pemphigoid, Takayasu arteritis, systemic slerosis, relapsingpolychondritis, refractory IgA nephropathy, SAPHO² syndrome (SAS),cytomegalovirus infection including rhinitis or cyst, psoriasis andmultiple myeloma.

The invention further provides pharmaceutical compositions comprisingcompounds having formula (I) or/and (IA), together with apharmaceutically acceptable carrier.

DETAIL DESCRIPTION

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood in the field to whichthe claimed subject matter belongs. In the event that there is aplurality of definitions for terms herein, those in this sectionprevail. Where reference is made to a URL or other such identifier oraddress, it is understood that such identifiers generally change andparticular information on the internet comes and goes, but equivalentinformation is found by searching the internet. Reference theretoevidences the availability and public dissemination of such information.

It is to be understood that the foregoing general description and thefollowing detailed description are exemplary and explanatory only andare not restrictive of any subject matter claimed. In this application,the use of the singular includes the plural unless specifically statedotherwise. It must be noted that, as used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. In thisapplication, the use of “or” means “and/or” unless stated otherwise.Furthermore, use of the term “including” as well as other forms, such as“include”, “includes,” and “included,” is not limiting.

Definition of standard chemistry and molecular biology terms are foundin reference works, including but not limited to, Carey and Sundberg“ADVANCED ORGANIC CHEMISTRY 4^(th) edition” Vols. A (2000) and B (2001),Plenum Press, New York and “MOLECULAR BIOLOGY OF THE CELL 5^(th)edition” (2007), Garland Science, New York. Unless otherwise indicated,conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry,biochemistry, recombinant DNA techniques and pharmacology arecontemplated within the scope of the embodiments disclosed herein.

Unless specific definitions are provided, the nomenclature employed inconnection with, and the laboratory procedures and techniques of,analytical chemistry, and medicinal and pharmaceutical chemistrydescribed herein are those generally used. In some embodiments, standardtechniques are used for chemical analyses, pharmaceutical preparation,formulation, and delivery, and treatment of patients. In otherembodiments, standard techniques are used for recombinant DNA,oligonucleotide synthesis, and tissue culture and transformation (e.g.,electroporation, lipofection). In certain embodiments, reactions andpurification techniques are performed e.g., using kits of manufacturer'sspecifications or as described herein. The foregoing techniques andprocedures are generally performed of conventional methods and asdescribed in various general and more specific references that are citedand discussed throughout the present specification.

As used herein the following definitions shall apply unless otherwiseindicated. Further many of the groups defined herein can be optionallysubstituted. The listing of substituents in the definition is exemplaryand is not to be construed to limit the substituents defined elsewherein the specification.

The term ‘alkyl’ refers to a straight or branched hydrocarbon chainradical consisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to eight carbon atoms, and which isattached to the rest of the molecule by a single bond, e.g., methyl,ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and1,1-dimethylethyl (t-butyl).

The term substituted or unsubstituted (C₁₋₂)alkyl refers to an alkylgroup as defined above having up to 2 carbon atoms, and the termsubstituted or unsubstituted (C₁₋₆)alkyl refers to an alkyl group asdefined above having up to 6 carbon atoms.

The term “alkenyl” refers to an aliphatic hydrocarbon group containing acarbon-carbon double bond which may be a straight or branched orbranched chain having about 2 to about 10 carbon atoms, e.g., ethenyl,1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-1-propenyl,1-butenyl, and 2-butenyl.

The term substituted or unsubstituted (C₂)alkenyl refers to an alkenylgroup as defined above having 2 carbon atoms.

The term “alkynyl” refers to a straight or branched chain hydrocarbylradicals having at least one carbon-carbon triple bond, and having inthe range of 2 up to 12 carbon atoms (with radicals having in the rangeof about 2 up to 10 carbon atoms presently being preferred), e.g.,ethynyl, propynyl, and butnyl.

The term substituted or unsubstituted (C₂) alkynyl refers to an alkynylgroup as defined above having 2 carbon atoms.

The term “alkoxy” denotes an alkyl group as defined above attached viaan oxygen linkage to the rest of the molecule. Representative examplesof these groups are —OCH₃ and —OC₂H₅.

The term “cycloalkyl” denotes a non-aromatic mono or multicyclic ringsystem of about 3 to 12 carbon atoms such as cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl. Examples of multicyclic cycloalkyl groupsinclude perhydronapththyl, adamantyl and norbornyl groups, bridgedcyclic groups, and sprirobicyclic groups, e.g., sprio (4,4) non-2-yl.

The term “cycloalkylalkyl” refers to a cyclic ring-containing radicalcontaining in the range of 3 up to 8 carbon atoms directly attached toan alkyl group which are then attached to the main structure at anycarbon from the alkyl group that results in the creation of a stablestructure such as cyclopropylmethyl, cyclobuyylethyl, andcyclopentylethyl.

The term “cycloalkenyl” refers to cyclic ring-containing radicalscontaining in the range of 3 up to 8 carbon atoms with at least onecarbon-carbon double bond such as cyclopropenyl, cyclobutenyl, andcyclopentenyl. The term “cycloalkenylalkyl” refers to a cycloalkenylgroup directly attached to an alkyl group which are then attached to themain structure at any carbon from the alkyl group that results in thecreation of a stable structure

The term “aryl” refers to an aromatic radical having in the range of 6up to 20 carbon atoms such as phenyl, naphthyl, tetrahydronapthyl,indanyl, and biphenyl.

The term “arylalkyl” refers to an aryl group as defined above directlybonded to an alkyl group as defined above. e.g., —CH₂C₆H₅ and —C₂H₅C₆H₅.

The term “heterocyclic ring” refers to a non-aromatic 3 to 15 memberring radical which, consists of carbon atoms and at least one heteroatomselected from the group consisting of nitrogen, phosphorus, oxygen andsulfur. For purposes of this invention, the heterocyclic ring radicalmay be a mono-, bi-, tri- or tetracyclic ring system, which may includefused, bridged or spiro ring systems, and the nitrogen, phosphorus,carbon, oxygen or sulfur atoms in the heterocyclic ring radical may beoptionally oxidized to various oxidation states. In addition, thenitrogen atom may be optionally quaternized. The heterocyclic ringradical may be attached to the main structure at any heteroatom orcarbon atom that results in the creation of a stable structure.

The term “heteroaryl” refers to an optionally substituted 5-14 memberaromatic ring having one or more heteroatoms selected from N, O, and Sas ring atoms. The heteroaryl may be a mono-, bi- or tricyclic ringsystem. Examples of such heteroaryl ring radicals include, but are notlimited to, oxazolyl, thiazolyl imidazolyl, pyrrolyl, furanyl,pyridinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl,benzothiazolyl, benzoxazolyl, carbazolyl, quinolyl and isoquinolyl. Theheteroaryl ring radical may be attached to the main structure at anyheteroatom or carbon atom that results in the creation of a stablestructure.

Examples of such “heterocyclic ring” or “heteroaryl” radicals include,but are not limited to, azetidinyl, acridinyl, benzodioxolyl,benzodioxanyl, benzofurnyl, carbazolyl, cinnolinyl, dioxolanyl,indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl,phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl, pteridinyl,purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl,tetrazoyl, imidazolyl, tetrahydroisouinolyl, piperidinyl, piperazinyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl,azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazinyl, pyrimidinyl,pyridazinyl, oxazolyl, oxazolinyl, oxasolidinyl, triazolyl, indanyl,isoxazolyl, isoxasolidinyl, morpholinyl, thiazolyl, thiazolinyl,thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl,isoindolyl, indolinyl, isoindolinyl, octahydroindolyl,octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl,benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl,benzooxazolyl, furyl, tetrahydrofurtyl, tetrahydropyranyl, thienyl,benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide thiamorpholinylsulfone, dioxaphospholanyl oxadiazolyl, chromanyl, and isochromanyl.

The term “heteroarylalkyl” refers to a heteroaryl ring radical asdefined above directly bonded to an alkyl group. The heteroarylalkylradical may be attached to the main structure at any carbon atom fromthe alkyl group that results in the creation of a stable structure.

The term “heterocyclyl” refers to a heterocylic ring radical as definedabove. The heterocylcyl ring radical may be attached to the mainstructure at any heteroatom or carbon atom that results in the creationof a stable structure.

The term “heterocyclylalkyl” refers to a heterocylic ring radical asdefined above directly bonded to an alkyl group. The heterocyclylalkylradical may be attached to the main structure at a carbon atom in thealkyl group that results in the creation of a stable structure.

The term “cyclic ring” refers to a cyclic ring containing 3-10 carbonatoms, optionally one or more of the ring carbon atoms may be replacedwith heteroatom such as N, O, or S atom.

The term “monocyclic ring” refers to a single cyclic ring containing3-10 carbon atoms, optionally one or more of the ring carbon atoms maybe replaced with heteroatom such as N, O, or S atom.

The prefix “monocyclic ring” being used such as for example monocyclicaryl, refers to single aryl ring wherein the aryl is as defined hereinabove. Similarly the term monocyclic heteroaryl refers to a singleheteroaryl ring wherein the heteroaryl is as defined herein above. Thesame is applicable to each of the terms monocyclic cycloalkyl andmonocyclic heterocyclic ring as well.

The term “substituted” unless otherwise specified, refers tosubstitution with any one or any combination of the followingsubstituents and may be the same or different which one or more areselected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo(═O), thio (═S), substituted or unsubstituted alkyl, substituted orunsubstituted alkoxy, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkenyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl,substituted or unsubstituted heterocyclic ring, substituted orunsubstituted heterocyclcyalkyl, substituted or unsubstituted aryl,substituted or unsubstituted arylalkyl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heteroarylalkyl, substituted orunsubstituted guanidine, —COOR^(x), —C(O)R^(x), —C(S)R^(x),—C(O)NR^(x)R^(y), —C(O)ONR^(x)R^(y), —NR^(y)R^(z), —NR^(x)CONR^(y)R^(z),—N(R^(x))SOR^(y), —N(R^(x))SO₂R^(y), —(═N—N(R^(x))R^(y)),—NR^(x)C(O)OR^(y), —NR^(x)R^(y), —NR^(x)C(O)R^(y)—,—NR^(x)C(S)R^(y)—NR^(x)C(S)NR^(y)R^(z), —SONR^(x)R^(y)—,—SO₂NR^(x)R^(y)—, —OR^(x), —OR^(x)C(O)NR^(y)R^(z), —OR^(x)C(O)OR^(y)—,—OC(O)R^(x), —OC(O)NR^(x)R^(y), —R^(x)NR^(y)C(O)R^(z), —R^(x)OR^(y),—R^(x)C(O)OR^(y), —R^(x)C(O)NR^(y)R^(z), —R^(x)C(O)R^(y),—R^(x)OC(O)R^(y), —SR, —SOR^(x), —SO₂R^(x), —ONO₂, wherein R^(x), R^(y)and R^(z) in each of the above groups can be hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkoxy, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl,substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted cycloalkenylalkyl, substituted or unsubstitutedheterocyclic ring, substituted or unsubstituted heterocyclcyalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedarylalkyl, substituted or unsubstituted heteroaryl, substituted orunsubstituted heteroarylalkyl, or any two of R^(x), R^(y) and R^(z) maybe joined to form a substituted or unsubstituted saturated orunsaturated 3-10 membered ring, which may optionally include heteroatomswhich may be the same or different and are selected from O, NR^(X) or S.Substitution or the combination of substituents envisioned by thisinvention are preferably those that result in the formation of a stableor chemically feasible compounds. The term stable as used herein refersto the compounds or the structure that are not substantially alteredwhen subjected to conditions to allow for their production, detectionand preferably their recovery, purification and incorporation into apharmaceutical composition.

The term “halogen” or “halo” refers to radicals of fluorine, chlorine,bromine and iodine.

The term “protecting group” or “PG” refers to a substituent that isemployed to block or protect a particular functionality. Otherfunctional groups on the compound may remain reactive. For example, an“amino-protecting group” is a substituent attached to an amino groupthat blocks or protects the amino functionality in the compound.Suitable amino-protecting groups include, but are not limited to,acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl(CBz) and 9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a“hydroxy-protecting group” refers to a substituent of a hydroxy groupthat blocks or protects the hydroxy functionality. Suitablehydroxy-protecting groups include, but are not limited to, acetyl andsilyl. A “carboxy-protecting group” refers to a substituent of thecarboxy group that blocks or protects the carboxy functionality.Suitable carboxy-protecting groups include, but are not limited to,—CH₂CH₂SO₂Ph, cyanoethyl, 2-(trimethylsilyl)ethyl,2-(trimethylsilyl)ethoxymethyl, -2-(p-toluenesulfonyl)ethyl,2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl, andnitroethyl. For a general description of protecting groups and theiruse, see T. W. Greene, Protective Groups in Organic Synthesis, JohnWiley & Sons, New York, 1991.

The term “stereoisomer” refers to compounds, which have identicalchemical composition, but differ with regard to arrangement of the atomsand the groups in space. These include enantiomers, diastereomers,geometrical isomers, atropisomer or conformational isomers.

All the stereoisomers of compounds described herein are within the scopeof this invention. Racemic mixtures are also encompassed within thescope of this invention. Therefore, single stereochemical isomers aswell enantiomeric, diastereoisomeric and geometric (or conformational)mixtures of the present compounds fall within the scope of theinvention.

The term “tautomers” refers to compounds, which are characterized byrelatively easy interconversion of isomeric forms in equilibrium. Theseisomers are intended to be covered by this invention.

The term “prodrug” refers to a compound, which is an inactive precursorof a compound, converted into its active form in the body by normalmetabolic processes.

The term “ester” refers to a compound, which is formed by reactionbetween an acid and an alcohol with elimination of water. An ester canbe represented by the formula RCOOR′.

Additionally the instant invention also includes the compounds whichdiffer only in the presence of one or more isotopically enriched atomsfor example replacement of Hydrogen with Deuterium and the like.

Pharmaceutically acceptable salts forming part of this invention includesalts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu,Zn, and Mn; salts of organic bases such as N,N′-diacetylethylenediamine,glucamine, triethylamine, choline, hydroxide, dicyclohexylamine,metformin, benzylamine, trialkylamine, thiamine, and the like; chiralbases like alkylphenylamine, glycinol, and phenyl glycinol, salts ofnatural amino acids such as glycine, alanine, valine, leucine,isoleucine, norleucine, tyrosine, cystine, cysteine, methionine,proline, hydroxy proline, histidine, ornithine, lysine, arginine, andserine; quaternary ammonium salts of the compounds of invention withalkyl halides, and alkyl sulphates such as MeI and (Me)₂SO₄, non-naturalamino acids such as D-isomers or substituted amino acids; guanidine,substituted guanidine wherein the substituents are selected from nitro,amino, alkyl, alkenyl, alkynyl, ammonium or substituted ammonium saltsand aluminum salts. Salts may include acid addition salts whereappropriate which are, sulphates, nitrates, phosphates, perchlorates,borates, hydrohalides, acetates, tartrates, maleates, citrates,fumarates, succinates, palmoates, methanesulphonates, benzoates,salicylates, benzenesulfonates, ascorbates, glycerophosphates, andketoglutarates. Pharmaceutically acceptable solvates may be hydrates orcomprise other solvents of crystallization such as alcohols.

Additionally the instant invention also includes the compounds whichdiffer only in the presence of one or more isotopically enriched atomsfor example replacement of hydrogen with deuterium.

The term “subject” or “patient” encompasses mammals and non-mammals.Examples of mammals include, but are not limited to, any member of theMammalian class: humans, non-human primates such as chimpanzees, andother apes and monkey species; farm animals such as cattle, horses,sheep, goats, and swine; domestic animals such as rabbits, dogs, andcats; and laboratory animals including rodents, such as rats, mice andguinea pigs. Examples of non-mammals include, but are not limited to,birds, fish and the like. In one embodiment of the methods andcompositions provided herein, the mammal is a human.

The terms “treat,” “treating” or “treatment,” as used herein, includealleviating, abating or ameliorating a disease, disorder or conditionsymptoms, preventing additional symptoms, ameliorating or preventing theunderlying causes of symptoms, inhibiting the disease, disorder orcondition, e.g., arresting the development of the disease, disorder orcondition, relieving the disease, disorder or condition, causingregression of the disease, disorder or condition, relieving a conditioncaused by the disease, disorder or condition, or stopping the symptomsof the disease, disorder or condition either prophylactically and/ortherapeutically.

As used herein, “amelioration” refers to an improvement in a disease orcondition or at least a partial relief of symptoms associated with adisease or condition and As used herein, amelioration of the symptoms ofa particular disease, disorder or condition by administration of aparticular compound or pharmaceutical composition refers to anylessening of severity, delay in onset, slowing of progression, orshortening of duration, whether permanent or temporary, lasting ortransient that are attributed to or associated with administration ofthe compound or composition.

The terms “inhibits”, “inhibiting”, or “inhibitor” of DHODH, as usedherein, refer to inhibition of the enzyme DHODH.

By “pharmaceutically acceptable,” as used herein, refers a material,such as a carrier or diluent, which does not abrogate the biologicalactivity or properties of the compound, and is relatively nontoxic,i.e., the material is administered to an individual without causingundesirable biological effects or interacting in a deleterious mannerwith any of the components of the composition in which it is contained.

The term “pharmaceutical composition” refers to a mixture of a compoundcapable of inhibiting DHODH as described herein with other chemicalcomponents, such as carriers, stabilizers, diluents, dispersing agents,suspending agents, thickening agents, and/or excipients. Thepharmaceutical composition facilitates administration of the compound toan organism. The compound and pharmaceutical composition of the presentinvention can be administered by various routes of administrationincluding, but not limited to, intravenous, oral, aerosol, parenteral,ophthalmic, pulmonary and topical administration.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of an agent or a compoundbeing administered which will relieve to some extent one or more of thesymptoms of the disease or condition being treated. The result isreduction and/or alleviation of the signs, symptoms, or causes of adisease, or any other desired alteration of a biological system. Forexample, an “effective amount” for therapeutic uses is the amount of thecomposition that includes a compound capable of inhibiting DHODH asdescribed herein required to provide a clinically significant decreasein disease symptoms. In some embodiments, an appropriate “effective”amount in any individual case is determined using techniques, such as adose escalation study.

The term “carrier,” as used herein, refers to relatively nontoxicchemical compounds or agents that facilitate the incorporation of acompound into cells or tissues.

The term “diluent” refers to chemical compounds that are used to dilutethe compound of interest prior to delivery. In some embodiments,diluents are used to stabilize compounds because they provide a morestable environment. Salts dissolved in buffered solutions (which alsoprovide pH control or maintenance) are utilized as diluents, including,but not limited to a phosphate buffered saline solution.

As used herein, the term “immune” include cells of the immune system andcells that perform a function or activity in an immune response, suchas, but not limited to, T-cells, B-cells, lymphocytes, macrophages,dendritic cells, neutrophils, eosinophils, basophils, mast cells, plasmacells, white blood cells, antigen presenting cells and natural killercells.

As used herein, “cytokine” or “cytokines” refers to small solubleproteins secreted by cells that in some embodiments, alter the behavioror properties of the secreting cell or another cell. Cytokines bind tocytokine receptors and trigger a behavior or property within the cell,for example, cell proliferation, death or differentiation. Exemplarycytokines include, but are not limited to, interleukins (e.g., IL-2,IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13,IL-15, IL-16, IL-17, IL-18, IL-1α, IL-1β, and IL-1 RA), granulocytecolony stimulating factor (G-CSF), granulocyte-macrophage colonystimulating factor (GM-CSF), oncostatin M, erythropoietin, leukemiainhibitory factor (LIF), interferons, B7.1 (also known as CD80), B7.2(also known as B70, CD86), TNF family members (TNF-α, TNF-β, LT-β, CD40ligand, Fas ligand, CD27 ligand, CD30 ligand, 4-1BBL, Trail), and MIF.

The compounds of the present invention are also useful in combination(administered together or sequentially) with known immunomodulatorsand/or anti-inflammatory agents useful in the treatment of autoimmunediseases, immune and inflammatory diseases, destructive bone disorders,malignant neoplastic diseases, angiogenic-related disorders, viraldiseases, and infectious diseases such as

-   -   Anti-TNF-alpha monoclonal antibodies such as Infliximab,        Certolizumab pegol, Golimumab, Adalimumab and AME-527 from        Applied Molecular Evolution,    -   Antimetabolite compounds such as Mizoribine, Cyclophosphamide        and Azathiopirine,    -   Calcineurin (PP-2B) Inhibitors/INS Expression Inhibitors such as        cyclosporine A, Tacrolimus and ISA-247 from Isotechnika,    -   Cyclooxygenase Inhibitors such as Aceclofenac, Diclofenac,        Celecoxib. Rofecoxib. Etoricoxib, Valdecoxib, Lumiracoxib,        Cimicoxib and LAS-34475 from Laboratorios Almirall, S.A.,    -   TNF-alpha Antagonists such as Etanercept, Lenercept, Onercept        and Pegsunercept,    -   NF-kappaB (NFKB) Activation Inhibitors such as Sulfasalazine and        Iguratimod,    -   IL-1 Receptor Antagonists such as Anakinra and AMG-719 from        Amgen,    -   Dihydrofolate Reductase (DHFR) Inhibitors such as Methrotexate,        Aminopterin and CH-1504 from Chelsea,    -   Inhibitors of Inosine 5′-Monophosphate Dehydrogenase (IMPDH)        such as Mizoribine, Ribavirin, Tiazofurin, Amitivir,        Mycophenolate mofetil, Ribamidine and Merimepodib,    -   Glucocorticoids such as Prednisolone, Methylprednisolone,        Dexamethasone, Cortisol, Hydrocortisone, Triamcinolone        acetonide, Fluocinolone acetonide, Fluocinonide, Clocortolone        pivalate, Hydrocortisone aceponate, Methylprednisolone        suleptanate,    -   Betamethasone butyrate propionate, Deltacortisone,        Deltadehydrocortisone, Prednisone, Dexamethasone sodium        phosphate, Triamcinolone, Betamethasone valerate, Betamethasone,        Hydrocortisone sodium succinate, Prednisolone sodium phosphate,        Hydrocortisone probutate and Difluprednate,    -   Anti-CD20 monoclonal antibodies such as Rituximab, Ofatumumab,        Ocrelizumab, Veltuzumab and TRU-015 from Trubion        Pharmaceuticals,    -   B-targeted cell therapies such as BLYSS, BAFF and TACI-Ig,    -   p38 Inhibitors such as AMG-548 (from Amgen), ARRY-797 (from        Array Biopharma), Chlormethiazole edisylate, Doramapimod,        PS-540446, BMS-582949 (from BMS), SB-203580, SB-242235,        SB-235699, SB-281832, SB-681323, SB-856553 (all from        GlaxoSmithKline), KC-706 (from Kemia), LEO-1606, LEO-15520 (all        from Leo), SC-80036, SD-06, PH-797804 (all from Pfizer),        RWJ-67657 (from R. W. Johnson), RO-3201195, RO-4402257 (all from        Roche), AVE-9940 (from Aventis). SCIO-323, SCIO-469 (all from        Scios), TA-5493 (from Tanabe Seiyaku), and VX-745, VX-702 (all        from Vertex).    -   Jak3 Inhibitors such as CP690550 from Pfizer, R-348    -   Syk inhibitors such as R-112, R-406 and Fostamatinib (R-788) all        from Rigel,    -   MEK inhibitors such as ARRY-142886, ARRY-438162 (all from Array        Biopharma), AZD-6244 (from AstraZeneca), PD-098059, PD-0325901        (all from Pfizer), AR-119, AS703026    -   P2X7 receptor antagonist such as AZD-9056 from AstraZeneca,    -   S1 P1 agonists such as Fingolimod, CS-0777 from Sankyo and        R-3477 from Actelion, ONO-4641, and KRP-203 from Novartis,    -   Anti-CD49 monoclonal antibodies such as Natalizumab,    -   Integrin Inhibitors such as Cilengitide, Firategrast,        Valategrast hydrochloride, SB-273005, SB-683698 (all from        Glaxo), HMR-1031 from Sanofi-Aventis, R-1295 from Roche,        BMS-587101 from BMS and CDP-323 from UCB Celltech,    -   Anti-CD88 monoclonal antibodies such as Eculizumab and        Pexelizumab,    -   IL-6 receptor antagonist such as CBP-1011 from InKine and C-326        from Amgen,    -   (w) Anti IL-6 monoclonal antibodies such as Elsilimomab,        CNTO-328 from Centocor and VX-30 from Vaccinex,    -   Anti-CD152 monoclonal antibodies such as lpilimumab and        Ticilimumab,    -   Fusion proteins comprising the extracellular domain of human        cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to        portions of human immunoglobulin G1 such as Abatacept,    -   Agents useful in the treatment of bone disorders such as        Bisphosphonates such as Tiludronate disodium, Clodronate        disodium, Disodium pamidronate, Etidronate disodium, Xydiphone        (K1Na salt), Alendronate sodium, Neridronate, Dimethyl-APD,        Olpadronic acid sodium salt, Minodronic acid, Apomine,        lbandronate sodium hydrate and Risedronate sodium,    -   VEGF Try kinase inhibitors such as Pegaptanib octasodium,        Vatalanib succinate,    -   Sorafenib, Vandetanib, Sunitinib malate, Cediranib, Pazopanib        hydrochloride and AE-941 from AEterna Zentaris,    -   Other compounds efficacious in autoimmune diseases such as Gold        salts, hydroxycloroquinine, Penicilamine, K-832, SMP114 and        AD452,    -   Purine-Nucleoside phosphorylase inhibitors such as Forodesine        hydrochloride, R-3421 from Albert Einstein College of Medicine,        CI-972 and CI-1000 both from Pfizer,    -   Anti-RANKL monoclonal antibodies such as Denosumab,    -   Anti-CD25 monoclonal antibodies such as Inolimomab, Dacliximab,        Basiliximab and LMB-2 from the US National Cancer Institute,    -   Histone Deacetylase (HDAC) Inhibitors such as Divalproex sodium,        Acetyldinaline, Depsipeptide, Sodium butyrate, Sodium        phenylbutyrate, Vorinostat, MS-27-275 from Mitsui, Valproic        acid, Pyroxamide, Tributyrin, PX-105684 from TopoTarget, MG-0103        from MethylGene, G2M-777 from TopoTarget and CG-781 from Celera        and    -   Anti colony-stimulating factor (GM-CSF) monoclonal antibodies        such as KB-002 from KaloBios.

The compounds of the invention are used for the treatment of rheumatoidarthritis, psoriatic arthritis, ankylosing spondilytis, multiplesclerosis, Wegener's granulomatosis, systemic lupus erythematosus,psoriasis and sarcoidosis it may be advantageous to use them incombination with other active compounds known to be useful in thetreatment of such diseases such as rheumatoid arthritis, psoriaticarthritis, ankylosing spondilytis, multiple sclerosis, Wegener'sgranulomatosis, systemic lupus erythematosus, psoriasis and sarcoidosis.

The combinations of the invention may be used in the treatment ofdiseases and/or disorders wherein the inhibition of DHODH is known toshow beneficial effect. Thus, the present application encompassesmethods of treatment of these disorders, as well as the use of thecombinations of the invention in the manufacture of a medicament for thetreatment of these disorders.

The compounds of the present invention are also useful in combination(administered together or sequentially) with known anti-cancertreatments such as radiation therapy or with cytostatic or cytotoxic oranticancer agents, such as for example, but not limited to, DNAinteractive agents, such as cisplatin or doxorubicin; topoisomerase IIinhibitors, such as etoposide; topoisomerase I inhibitors such as CPT-11or topotecan; tubulin interacting agents, such as paclitaxel, docetaxelor the epothilones (for example ixabepilone), either naturally occurringor synthetic; hormonal agents, such as tamoxifen; thymidilate synthaseinhibitors, such as 5-fluorouracil; and anti-metabolites, such asmethotrexate, other tyrosine kinase inhibitors such as Iressa andOSI-774; angiogenesis inhibitors; EGF inhibitors; VEGF inhibitors; CDKinhibitors; SRC inhibitors; c-Kit inhibitors; Her1/2 inhibitors andmonoclonal antibodies directed against growth factor receptors such aserbitux (EGF) and herceptin (Her2) and other protein kinase modulatorsas well.

In some embodiments, diseases, disorders or conditions that are treatedor prevented using compounds disclosed herein that are capable ofinhibiting DHODH, compositions thereof, and methods provided herein toidentify compounds capable of inhibiting DHODH, include diseases,conditions or disorders involving inflammation and/or that are relatedto the immune system. These diseases include but are not limited toasthma, chronic obstructive pulmonary disease, rheumatoid arthritis,inflammatory bowel disease, glomerulonephritis, neuroinflammatorydiseases such as multiple sclerosis, and disorders of the immune system.

Thus, in some embodiments, inhibition of DHODH results in a method fortreating immune and immune-related disorders, including, for example,chronic immune diseases/disorders, acute immune diseases/disorders,autoimmune and immunodeficiency diseases/disorders, diseases/disordersinvolving inflammation, organ transplant graft rejections andgraft-versus-host disease and altered (e.g., hyperactive) immuneresponses.

Examples of immune disorders include psoriasis, rheumatoid arthritis,vasculitis, inflammatory bowel disease, dermatitis, osteoarthritis,asthma, inflammatory muscle disease, allergic rhinitis, vaginitis,interstitial cystitis, scleroderma, osteoporosis, eczema, allogeneic orxenogeneic transplantation (organ, bone marrow, stem cells and othercells and tissues) graft rejection, graft-versus-host disease, lupuserythematosus, inflammatory disease, type I diabetes, pulmonaryfibrosis, dermatomyositis, Sjogren's syndrome, thyroiditis (e.g.,Hashimoto's and autoimmune thyroiditis), myasthenia gravis, autoimmunehemolytic anemia, multiple sclerosis, cystic fibrosis, chronic relapsinghepatitis, primary biliary cirrhosis, allergic conjunctivitis and atopicdermatitis.

In other embodiments, compounds disclosed herein that are capable ofinhibiting DHODH, compositions thereof, and methods provided herein toidentify compounds capable of modulating DHODH inhibitors, are used inconnection with treatment of malignancies, including, but not limitedto, malignancies of lymphoreticular origin, bladder cancer, breastcancer, colon cancer, endometrial cancer, head and neck cancer, lungcancer, melanoma, ovarian cancer, prostate cancer and rectal cancer.DHODH is thought to play an important role in cell proliferation incancer cells.

The following general methodology described herein provides the mannerand process of making and using the compound of the present inventionand are illustrative rather than limiting. Further modification ofprovided methodology and additionally new methods may also be devised inorder to achieve and serve the purpose of the invention. Accordingly, itshould be understood that there may be other embodiments which fallwithin the spirit and scope of the invention as defined by thespecification hereto.

General Method of Preparation of Compounds of the Invention

The compounds of the present invention may be prepared by the followingprocesses. Unless otherwise indicated, the variables (e.g. A, B, Cy, R¹,R, Y, L₁, X, X₁, X₂, X₃ and L₂) when used in the below formulae are tobe understood to present those groups described above in relation toformula (I) to (IA).

Scheme 1:

This scheme provides a method for the preparation of a compound offormula (I) wherein A is a substituted or unsubstituted monocyclic aryland substituted or unsubstituted monocyclic heteroaryl and othervariables such as B, Cy, R¹, R, Y, L₁, X, X₁, X₂, X₃ and L₂ are the sameas described above in relation to formula (I).

The compound of formula (1) wherein Lg is a leaving group such ashydroxyl or halogen, can be coupled with a compound of formula (2) in asuitable solvent using an amide coupling reagent such as DCC oroptionally in the presence of a suitable base to give an intermediate(for example R¹ is COOEt) which can then be transformed either in singleor multiple steps to the desired compound of formula (I), for example toR¹ is COOH wherein A is a substituted or unsubstituted monocyclic arylor a substituted or unsubstituted monocyclic heteroaryl and othervariables such as L, B, Cy, R², R³, R⁴, m and n are the same asdescribed above in relation to formula (I).

Scheme 2:

This scheme provides a method for the preparation of a compound offormula (I) wherein R¹ is COOH, L₂ is absent, and other variables suchas A, B, Cy, R¹, R, Y, L₁, X, X₁, X₂, and X₃ are the same as describedabove in relation to formula (I).

The compound of formula (3), wherein Hal represents halogen, can becoupled with a compound of formula (4) in the presence of Pd(PPh₃)₄ anda metal carbonate such as K₂CO₃ (Suzuki coupling) to give a compound offormula (2a). The compound of formula (2a) can be reacted with asuitable compound of formula (Ia) in the presence of a suitable solventto give the desired compound of formula (I) wherein R¹ is COOH, L₂ isabsent and other variables such as A, B, Cy, R, Y, L₁, X, X₁, X₂, and X₃are the same as described above in relation to formula (I).

Scheme 3:

This scheme provides a method for the preparation of a compound offormula (I) wherein R¹ is COOH, L₂ is —O—, and other variables such asA, B, Cy, R¹, R, Y, L₁, X, X₁, X₂, X₃ and n are the same as describedabove in relation to formula (I).

The compound of formula (1a) can be reacted with a suitable compound offormula (2a) wherein Hal represents halogen in the presence of asuitable solvent to give the desired compound of formula (5). Thecompound of formula (5) can be coupled with a compound of formula (6) inthe presence of a suitable base such as K₂CO₃ to give the desiredcompound of formula (I) wherein R¹ is COOH, L₂ is —O— and othervariables such as A, B, Cy, R, Y, L₁, X, X₁, X₂, and X₃ are the same asdescribed above in relation to formula (I).

Similar methodologies with certain modifications as known to thoseskilled in the art can be used to synthesize compound of formula (I)or/and (IA), wherein the variables are to be understood to present thosegroups described above in relation to formula (I) or/and (IA), usingsuitable intermediates and reagents.

EXPERIMENTAL

Unless otherwise mentioned, work-up implies distribution of reactionmixture between the aqueous and organic phases indicated withinparenthesis, separation and drying over Na₂SO₄ of the organic layer andevaporating the solvent to give a residue. Unless otherwise stated,purification is by column chromatography using silica gel as thestationary phase and a mixture of petroleum ether (boiling at 60-80° C.)and ethyl acetate or dichloromethane and methanol of suitable polarityas the mobile phases. RT refers to ambient temperature (25-28° C.).

General Procedure—for Suzuki Coupling:

To a solution of an aryl bromide (1 eq.) in dioxane and water (5:1) wereadded an arylboronic acid or an arylboronic acid pinacol ester (1.3 eq),tetrakis(triphenylphosphine)palladium(0)-(0.08 eq) and potassiumcarbonate (3.3 eq). The mixture was degassed with N₂ for 30 min. andrefluxed until both the staRTing materials disappeared as monitored byTLC. Work-up (H₂O/AcOEt) and purification gave the desired product.

Intermediates 1, 4-27, 32-54, 56-63, 65-84 and 86-89 were prepared usinggeneral procedure-1.

Intermediate 1: 3,5-difluoro-3′-methoxybiphenyl-4-amine

The title compound (992 mg) was prepared from 2,6-difluoro-4-bromoaniline (1.1 g, 5.3 mmol) and 3-methoxyphenylboronic acid (1.04 g, 6.8mmol) as a pale-yellow liquid. ¹H-NMR (δ ppm, CDCl₃+DMSO-d₆, 400 MHz):7.21-7.20 (m, 1H), 6.99-6.89 (m, 3H), 6.87-6.83 (m, 1H), 6.74-6.68 (m,1H), 3.97 (bs, 2H), 3.69 (s, 3H).

Intermediate 2: 2-(3-methoxyphenyl)-5-nitropyridine

The title compound (612 mg) was prepared from 2-chloro-5-nitropyridine(500 mg, 3.15 mmol) and 3-methoxyphenylboronic acid (623 mg, 4.1 mmol)as a pale yellow solid. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 9.50 (d, J 2.6,1H), 8.53 (dd, J 2.6, 8.8, 1H), 7.91 (d, J 8.8, 1H), 7.69-7.68 (m, 1H),7.63 (d, J 7.8, 1H), 7.44 (t, J 7.9, 1H), 7.08-7.05 (m, 1H), 3.91 (s,3H).

Intermediate 3: 6-(3-methoxyphenyl)pyridin-3-amine

Iron powder (739 mg, 13.24 mmol) and ammonium chloride (100 mg, 3.18mmol) were added to a solution of intermediate 2 (610 mg, 2.65 mmol) inEtOH/H₂O (2:1, 15 mL) and the mixture refluxed for one hour. The mixturewas filtered through celite and celite washed with ethanol. Work-up(H₂O/AcOEt) and concentration of the combined layers affordedintermediate 3 (330 mg) as a waxy solid. ¹H-NMR (δ ppm, DMSO-d₆, 400MHz): 8.00 (d, J 2.7, 1H), 7.61 (d, J 8.5, 1H), 7.47-7.45 (m, 2H), 7.27(t, J 8, 1H), 6.97 (dd, J 2.8, 8.5, 1H), 6.83-6.81 (m, 1H), 5.46 (s,2H), 3.78 (s, 3H).

Intermediate 4: 3′-ethoxy-3-fluorobiphenyl-4-amine

The title compound (1.34 g) was prepared from 2-fluoro-4-bromo aniline(2.5 g, 13.1 mmol) and 3-ethoxyphenylboronic acid (2.8 g, 17.0 T mmol)as a pale-yellow liquid. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 7.38-7.20 (m,3H), 7.10 (d, J 7.9, 1H), 7.07-7.05 (m, 1H), 6.83-6.76 (m, 2H), 5.24 (s,2H), 4.06 (q, J 7, 2H), 1.32 (t, J 7, 3H).

Intermediate 5: 3′-ethoxy-3,5-difluorobiphenyl-4-amine

The title compound (0.219 g) was prepared from 2,6-difluoro-4-bromoaniline (0.5 g, 2.4 mmol) and 3-ethoxyphenylboronic acid (0.517 g, 3.12mmol) as a pale-yellow liquid. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz):7.30-7.24 (m, 3H), 7.14 (d, J 7.9, 1H), 7.11 (s, 1H), 6.82 (dd, J 2.1,8.1, 1H), 5.31 (s, 2H), 4.07 (q, J 7, 2H), 1.32 (t, J 7, 3H).

Intermediate 6: 2′-chloro-3,5-difluorobiphenyl-4-amine

The title compound (0.140 g) was prepared from 2,6-difluoro-4-bromoaniline (0.22 g, 1.06 mmol) and 2-chlorophenylboronic acid (0.21 g, 1.38mmol) as a white solid. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 7.52-7.50 (m,1H), 7.40-7.35 (m, 3H), 7.00 (d, J 2.1, 7.6, 2H), 5.39 (s, 2H).

Intermediate 7: 3,5-difluorobiphenyl-4-amine

The title compound (0.401 g) was prepared from 2,6-difluoro-4-bromoaniline (0.5 g, 2.4 mmol) and phenylboronic acid (0.38 g, 3.12 mmol) asa white solid. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 7.60 (d, J 7.4, 2H),7.38 (t, J 7.5, 2H), 7.30-7.25 (m, 3H), 5.33 (s, 2H).

Intermediate 8: 3,5-difluoro-3′-(trifluoromethoxy)biphenyl-4-amine

The title compound (0.812 g) was prepared from 2,6-difluoro-4-bromoaniline (1 g, 4.8 mmol) and 3-(trifluoromethoxy)phenylboronic acid (1.28g, 6.24 mmol) as a colourless liquid.

Intermediate 9: 3′-(benzyloxy)-3,5-difluorobiphenyl-4-amine

The title compound (0.143 g) was prepared from 2,6-difluoro-4-bromoaniline (0.3 g, 1.4 mmol) and 3-(benzyloxy)phenylboronic acid (0.426 g,1.8 mmol) as a colourless liquid. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz):7.49-7.44 (m, 2H), 7.39 (t, J 7.2, 2H), 7.35-7.26 (m, 4H), 7.24 (s, 1H),7.18 (d, J 7.8, 1H), 6.91 (dd, J 1.9, 8.0, 1H), 5.33 (s, 2H), 5.16 (s,2H).

Intermediate 10: 3-chloro-3′-ethoxy-5-fluorobiphenyl-4-amine

The title compound (0.360 g) was prepared from4-bromo-2-chloro-6-fluoroaniline (0.5 g, 2.0 mmol) and3-ethoxyphenylboronic acid (0.441 g, 2.65 mmol) as a yellow liquid.¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 7.43-7.38 (m, 2H), 7.27 (t, J 7.9,1H), 7.14 (d, J 7.9, 1H), 7.10 (s, 1H), 6.82 (dd, J 2.1, 8.1, 1H), 5.51(s, 2H), 4.07 (q, J 7, 2H), 1.32 (t, J 7, 3H).

Intermediate 11: 3,5-dichloro-3′-methoxybiphenyl-4-amine

The title compound (0.550 g) was prepared from2,6-dichloro-4-bromoaniline (0.5 g, 2.0 mmol) and 3-methoxyphenylboronicacid (0.409 g, 2.69 mmol) as a white solid. ¹H-NMR (δ ppm, DMSO-d₆, 400MHz): 7.58 (s, 2H), 7.29 (t, J 7.8, 1H), 7.18-7.10 (m, 2H), 6.85 (dd, J2, 8.1, 1H), 5.63 (s, 2H), 3.81 (s, 3H).

Intermediate 12: 3-chloro-5-fluoro-3′-propoxybiphenyl-4-amine

The title compound (0.273 g) was prepared from4-bromo-2-chloro-6-fluoroaniline (0.5 g, 2.2 mmol) and3-propoxyphenylboronic acid (0.521 g, 2.9 mmol) as a yellow liquid.¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 7.44-7.39 (m, 3H), 7.27 (t, J 7.9,1H), 7.16-7.10 (m, 2H), 5.51 (s, 2H), 3.97 (t, J 6.5, 2H), 1.75-1.70 (m,2H), 0.98 (t, J 7.9, 3H).

Intermediate 13: 3-chloro-2′,5-difluorobiphenyl-4-amine

The title compound (0.392 g) was prepared from4-bromo-2-chloro-6-fluoroaniline (0.5 g, 2.2 mmol) and2-fluorophenylboronic acid (0.363 g, 2.6 mmol) as a pale-yellow liquid.¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 7.51 (td, J 1.7, 7.8, 1H), 7.38-7.32(m, 1H), 7.28 (s, 2H), 7.27-7.22 (m, 2H), 5.62 (s, 2H).

Intermediate 14: 3,5-dichloro-3′-ethoxybiphenyl-4-amine

The title compound (0.550 g) was prepared from4-Bromo-2,6-dichloroaniline (0.5 g, 2.2 mmol) and 3-ethoxyphenylboronicacid (0.447 g, 2.7 mmol) as a yellow liquid which was about 70% pure asadjudged by ¹H-NMR data. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 7.56 (s, 2H),7.28 (s, 1H), 7.16-7.08 (m, 2H), 6.83 (dd, J 2, 8.1, 1H), 5.62 (s, 2H),4.10 (q, J 7, 2H), 1.32 (t, J 7, 3H).

Intermediate 15: 3-fluoro-3′-(trifluoromethoxy)biphenyl-4-amine

The title compound (0.5 g) was prepared from 4-Bromo-2-fluoroaniline (1g, 5.3 mmol) and 3-(trifluoromethoxy)phenylboronic acid (1.4 g, 6.8mmol) as a yellow liquid. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 7.62 (d, J8, 1H), 7.53 (s, 1H), 7.48 (t, J 8, 1H), 7.42 (dd, J 2, 9.1, 1H), 7.28(dd, J 2, 8.3, 1H), 7.23 (d, J 11, 1H), 6.82 (t, J 8.5, 1H), 5.40 (s,2H).

Intermediate 16: 2′-fluoro-3-(trifluoromethoxy)biphenyl-4-amine

The title compound (0.294 g) was prepared from2-trifluoromethoxy-4-bromo aniline (0.5 g, 1.9 mmol) and2-fluorophenylboronic acid (0.345 g, 2.5 mmol) as a yellow liquid.¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 7.47 (td, J 1.2, 4.7, 1H), 7.33-7.20(m, 5H), 6.89 (d, J 8.8, 1H), 5.62 (s, 2H).

Intermediate 17: 3,5-dichloro-2′-fluorobiphenyl-4-amine

The title compound (0.367 g) was prepared from 4-Bromo-2,6-dichloroaniline (0.5 g, 1.9 mmol) and 2-fluorophenylboronic acid (0.363 g, 2.6mmol) as a white solid. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 7.50 (t, J6.3, 1H), 7.43 (s, 2H), 7.39-7.31 (m, 1H), 7.29-7.21 (m, 2H), 5.73 (s,2H).

Intermediate 18: 3,5-difluoro-3′-isopropoxybiphenyl-4-amine

The title compound (0.34 g) was prepared from 4-Bromo-2,6-difluoroaniline (0.5 g, 2.4 mmol) and 3-isopropoxyphenylboronic acid (0.337 g,3.1 mmol) as a red liquid. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 7.30-7.22(m, 3H), 7.16-7.07 (m, 2H), 6.89 (dd, J 2.3, 8.1, 1H), 5.32 (s, 2H),4.68 (septet, J 6, 1H), 1.26 (d, J 6, 6H).

Intermediate 19: 3,5-difluoro-3′-propoxybiphenyl-4-amine

The title compound (0.3 g) was prepared from 4-Bromo-2,6-difluoroaniline (0.5 g, 2.4 mmol) and 3-propoxyphenylboronic acid (0.337 g, 3.1mmol) as a red liquid. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 7.30-7.24 (m,3H), 7.18-7.10 (m, 2H), 6.86-6.80 (m, 1H), 5.31 (s, 2H), 3.97 (t, J 6.5,2H), 1.75-1.65 (m, 2H), 0.98 (t, J 7.4, 3H).

Intermediate 20: 2′,3-dichloro-5-fluorobiphenyl-4-amine

The title compound (0.260 g) was prepared from4-bromo-2-chloro-6-fluoroaniline (0.5 g, 2.4 mmol) and2-chlorophenylboronic acid (0.453 g, 2.9 mmol) as a white solid. ¹H-NMR(δ ppm, DMSO-d₆, 400 MHz): 7.60 (d, J 7.3, 1H), 7.42-7.31 (m, 3H),7.18-7.11 (m, 2H), 5.6 (s, 2H).

Intermediate 21: 3′-butoxy-3-chloro-5-fluorobiphenyl-4-amine

The title compound (0.190 g) was prepared from4-bromo-2-chloro-6-fluoroaniline (0.2 g, 0.89 mmol) and3-butoxyphenylboronic acid (0.224 g, 1.16 mmol) as a yellow solid.¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 7.44-7.41 (m, 2H), 7.27 (t, J 7.9,1H), 7.17-7.10 (m, 2H), 6.81-6.84 (m, 1H), 5.50 (s, 2H), 4.01 (t, J 5.3,2H), 1.72-1.65 (m, 2H), 1.50-1.41 (m, 2H), 0.93 (t, J 7.4, 3H).

Intermediate 22: 3-chloro-5-fluoro-3′-isobutoxybiphenyl-4-amine

The title compound (0.180 g) was prepared from4-bromo-2-chloro-6-fluoroaniline (0.2 g, 0.89 mmol) and3-isobutoxyphenylboronic acid (0.224 g, 1.16 mmol) as a yellow solid.¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 7.44-7.41 (m, 2H), 7.27 (t, J 7.9,1H), 7.17-7.10 (m, 2H), 6.84-6.81 (m, 1H), 5.50 (s, 2H), 3.83 (d, J 6.5,2H), 2.07-1.97 (m, 1H), 1.00 (d, J 6.7, 6H).

Intermediate 23: 2′,3,5-trifluorobiphenyl-4-amine

The title compound (0.492 g) was prepared from4-bromo-2,6-difluoroaniline (0.5 g, 2.4 mmol) and 2-fluorophenylboronicacid (0.436 g, 3.12 mmol) as a yellow liquid. ¹H-NMR (δ ppm, DMSO-d₆,400 MHz): 7.51 (td, J 1.5, 7.9, 1H), 7.38-7.31 (m, 1H), 7.29-721 (m,2H), 7.14 (d, J 8.6, 2H), 5.44 (s, 2H).

Intermediate 24: 2′,3,5-trichlorobiphenyl-4-amine

The title compound (0.4 g) was prepared from 4-bromo-2,6-dichloroaniline(0.5 g, 2.1 mmol) and 2-chlorophenylboronic acid (0.421 g, 2.7 mmol) asa white solid. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 7.55-7.50 (m, 1H),7.40-7.32 (m, 3H), 7.29 (s, 2H), 5.72 (s, 2H).

Intermediate 25: 3,5-difluoro-3′-isobutoxybiphenyl-4-amine

The title compound (0.16 g) was prepared from4-bromo-2,6-difluoroaniline (0.2 g, 0.96 mmol) and3-isobutoxyphenylboronic acid (0.242 g, 1.2 mmol) as a yellow liquid.

Intermediate 26: 3,5-difluoro-3′-butoxybiphenyl-4-amine

The title compound (0.104 g) was prepared from4-bromo-2,6-difluoroaniline (0.2 g, 0.96 mmol) and 3-butoxyphenylboronicacid (0.242 g, 1.2 mmol) as a colourless liquid.

Intermediate 27: 3-chloro-5-fluoro-3′-(trifluoromethoxy)biphenyl-4-amine

The title compound (0.280 g) was prepared from4-bromo-2-chloro-6-difluoroaniline (0.5 g, 2.27 mmol) and3-(trifluoromethoxy)phenylboronic acid (0.6 g, 2.89 mmol) as apale-yellow liquid. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 7.68-7.64 (m, 1H),7.62 (s, 1H), 7.53-7.46 (m, 3H) 7.29-7.22 (m, 1H), 5.64 (s, 2H).

Intermediate 28: 5-(benzyloxy)-1,3-difluoro-2-nitrobenzene

Potassium carbonate (544 mg, 3.94 mmol) and benzyl alcohol (0.3 ml, 2.8mmol) were added to a solution of 2,4,6-trifluoronitrobenzene (500 mg,2.8 mmol) in DMF (5 ml). This mixture was stirred at RT overnight. Workup (EtOAc/H₂O) afforded the title compound (521 mg) as a yellow liquidwhich was used in the next step without fuRTher purification.

Intermediate 29: 4-(benzyloxy)-2,6-difluoroaniline

Iron powder (502 mg, 9 mmol) and ammonium chloride (192 mg, 3.6 mmol)were added to a solution of intermediate 28 (500 mg, 1.8 mmol) inEtOH/H₂O (2:1, 15 mL) and the mixture refluxed for two hours. Themixture was filtered through celite and celite washed with ethanol.Work-up (H₂O/AcOEt) from the combined filtrates and purification ofafforded the title compound (24 mg) as a colourless liquid. ¹H-NMR (δppm, DMSO-d₆, 400 MHz): 7.42-7.36 (m, 3H), 7.35-7.28 (m, 2H), 6.68 (dd,J 1.6, 8.8, 2H), 4.97 (s, 2H), 4.64 (s, 2H).

Intermediate 30:1-bromo-3-(cyclopentyloxy)benzene

Potassium carbonate (400 mg, 2.8 mmol) was added to 3-Bromophenol (500mg, 2.8 mmol) dissolved in acetonitrile and the mixture was refluxed for1 h and cooled to RT. cyclopentyl bromide (430 mg, 2.8 mmol) was addedand the mixture refluxed again overnight. Work up (H₂O/EtOAc) andpurification afforded the title compound as a pale-yellow liquid. ¹H-NMR(δ ppm, CDCl₃, 400 MHz): 7.11 (t, J 8.3, 1H), 7.05-7.00 (m, 2H),6.82-6.76 (m, 1H), 4.76-4.68 (m, 1H), 1.94-1.73 (m, 6H), 1.65-1.54 (m,2H).

Intermediate 31:2-(3-(cyclopentyloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A mixture of intermediate 30 (335 mg, 1.4 mmol), bis(pinacolato)diboron(351 mg, 1.4 mmol) and potassium acetate (450 mg, 4.6 mmol) in dioxanewas degassed with N₂ for 30 min. Tetrakis(triphenylphosphine)palladium(0) (128 mg, 0.11 mmol) was added and the degassing continued again forfuRTher 15 min. This mixture was refluxed overnight. After completion ofthe reaction, work up (H₂O/EtOAc) and column purification afforded thetitle compound (165 mg) as a yellow liquid.

Intermediate 32: 3′-(cyclopentyloxy)-3,5-difluorobiphenyl-4-amine

The title compound (22 mg) was prepared from 4-bromo-2,6-difluoroaniline(165 mg, 0.6 mmol) and intermediate 31 (120 mg, 0.6 mmol) as apale-yellow liquid. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 7.29-7.22 (m, 3H),7.12 (d, J 8, 1H), 7.06 (s, 1H), 6.82-6.76 (m, 1H), 5.30 (s, 2H),4.96-4.88 (m, 1H), 1.96-1.82 (m, 2H), 1.75-1.65 (m, 4H), 1.60-1.51 (m,2H).

Intermediate 33: 3-chloro-3′-(cyclopentyloxy)-5-fluorobiphenyl-4-amine

The title compound (450 mg) was prepared from4-bromo-2-chloro-6-fluoroaniline (600 mg, 2.7 mmol) and intermediate 31(1 g, 3.4 mmol) as a yellow liquid. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz):7.42-7.36 (m, 2H), 7.26 (t, J 8, 1H), 7.11 (d, J 7.8, 1H), 7.08-7.05 (m,1H), 6.80 (dd, J 2.3, 8.1, 1H), 5.49 (s, 2H), 4.92-4.84 (m, 1H),1.97-1.87 (m, 2H), 1.77-1.62 (m, 4H), 1.60-1.50 (m, 2H).

Intermediate 34: 3′-(difluoromethoxy)-3,5-difluorobiphenyl-4-amine

The title compound (144 mg) was prepared from4-bromo-2,6-difluoroaniline (200 mg, 0.96 mmol) and3-(difluoromethoxy)phenylboronic acid (234 mg, 1.25 mmol) as a whitesolid. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 7.49 (d, J 7.9, 1H), 7.43-7.39(m, 2H), 7.38-7.30 (m, 2H), 7.32 (t, J 74, 1H), 7.06 (dd, J 1.8, 7.9,1H), 5.42 (s, 2H).

Intermediate 35:2-[3′-(difluoromethoxy)-3,5-difluorobiphenyl-4-ylcarbamoyl]benzoic acid

The title compound (155 mg) was prepared from4-bromo-2-chloro-6-fluoroaniline (89 mg, 1.16 mmol) and3-(difluoromethoxy)phenylboronic acid (217 mg, 1.16 mmol) as a whitesolid. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 7.52-7.47 (m, 3H), 7.46-7.44(m, 1H), 7.43-7.40 (m, 2H), 7.32 (t, J 74.2, 1H), 5.60 (s, 2H).

Intermediate 36: 2′-chloro-3,5-difluoro-5′-methoxybiphenyl-4-amine

The title compound (97 mg) was prepared from 4-bromo-2,6-difluoroaniline(100 mg, 0.48 mmol) and 2-chloro-5-methoxyphenylboronic acid (116 mg,0.62 mmol) as a yellow solid. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 7.40 (d,J 9.6, 1H), 7.02 (d, J 7.7, 2H), 6.92 (s, 2H), 5.39 (s, 2H), 3.77 (s,3H).

Intermediate 37: 3,3′,5-trifluoro-5′-methoxybiphenyl-4-amine

The title compound (51 mg) was prepared from 4-bromo-2,6-difluoroaniline(100 mg, 0.48 mmol) and 3-fluoro-5-methoxyphenylboronic acid (106 mg,0.62 mmol) as a yellow solid. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 7.35(dd, J 2.1, 8.1, 2H), 7.06 (d, J 10.2, 1H), 7.01 (s, 1H), 6.71 (dd, J 2,8.8, 1H), 5.42 (s, 2H), 3.81 (s, 3H).

Intermediate 38: 4-(benzo[d][1,3]dioxol-5-yl)-2,6-difluoroaniline

The title compound (143 mg) was prepared from4-bromo-2,6-difluoroaniline (200 mg, 0.96 mmol) andbenzo[d][1,3]dioxol-5-ylboronic acid (207 mg, 1.25 mmol) as a whitesolid. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 7.23-7.18 (m, 3H), 7.08 (dd, J1.8, 8.2, 1H), 6.91 (d, J 8.1, 1H), 6.01 (s, 2H), 5.24 (s, 2H).

Intermediate 39: 4-(benzo[d][1,3]dioxol-5-yl)-2-chloro-6-fluoroaniline

The title compound (143 mg) was prepared from4-bromo-2-chloro-6-fluoroaniline (200 mg, 0.89 mmol) andbenzo[d][1,3]dioxol-5-ylboronic acid (192 mg, 1.16 mmol) as a whitesolid. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 7.36-7.30 (m, 2H), 7.20 (d, J1.7, 1H), 7.06 (dd, J 1.4, 8.1, 1H), 6.91 (d, J 8.1, 1H), 6.01 (s, 2H),5.42 (s, 2H).

Intermediate 40: 3,5-difluoro-3′,4′-dimethoxybiphenyl-4-amine

The title compound (39 mg) was prepared from 4-bromo-2,6-difluoroaniline(100 mg, 0.48 mmol) and 3,4-dimethoxyphenylboronic acid (113 mg, 0.62mmol) as a pale-yellow solid. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 7.25(dd, J 2, 8.3, 2H), 7.18-7.10 (m, 2H), 6.94 (d, J 8.4, 1H), 5.21 (s,2H), 3.81 (s, 3H), 3.75 (s, 3H).

Intermediate 41: 3-chloro-3′,5-difluoro-5′-methoxybiphenyl-4-amine

The title compound (71 mg) was prepared from4-bromo-2-chloro-6-fluoroaniline (100 mg, 0.44 mmol) and3-fluoro-5-methoxyphenylboronic acid (97 mg, 0.57 mmol) as a pale-yellowsolid. ¹H-NMR (8 ppm, DMSO-d₆, 400 MHz): 7.51-7.45 (m, 2H), 7.05 (d, J10.3, 1H), 7.00 (s, 1H), 6.73 (dd, J 2.1, 4.2, 1H), 5.60 (s, 2H), 3.81(s, 3H).

Intermediate 42: 3,3′-dichloro-5-fluoro-5′-methoxybiphenyl-4-amine

The title compound (41 mg) was prepared from4-bromo-2-chloro-6-fluoroaniline (100 mg, 0.44 mmol) and3-chloro-5-methoxyphenylboronic acid (107 mg, 0.57 mmol) as apale-yellow solid.

Intermediate 43: 4-(2,3-dihydrobenzofuran-5-yl)-2,6-difluoroaniline

The title compound (182 mg) was prepared from4-bromo-2,6-difluoroaniline (200 mg, 0.96 mmol) and2,3-dihydrobenzofuran-5-ylboronic acid (204 mg, 1.25 mmol) as a whitesolid. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 7.46 (s, 1H), 7.30 (dd, J 1.8,8.3, 1H), 7.16 (dd, J 2.1, 8.2, 2H), 6.75 (d, J 8.3, 1H), 5.18 (s, 2H),4.52 (t, J 8.7, 2H), 3.18 (t, J 8.5, 2H).

Intermediate 44: 2-chloro-4-(2,3-dihydrobenzofuran-5-yl)-6-fluoroaniline

The title compound (86 mg) was prepared from4-bromo-2-chloro-6-fluoroaniline (200 mg, 0.89 mmol) and2,3-dihydrobenzofuran-5-ylboronic acid (189 mg, 1.16 mmol) as apale-yellow solid. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 7.46 (s, 1H),7.33-7.25 (m, 3H), 6.75 (d, J 8.3, 1H), 5.36 (s, 2H), 4.52 (t, J 8.7,2H), 3.18 (t, J 8.6, 2H).

Intermediate 45: 4-(1,3-dimethyl-1H-indazol-5-yl)-2,6-difluoroaniline

Potassium acetate (0.344 g, 3.51 mmol) and bis(pinacolato)diboron (351mg, 1.4 mmol) were added to a solution of5-bromo-1,3-dimethyl-1H-indazole (240 mg, 1.06 mmol) in dioxane (10 ml)and mixture was degassed with nitrogen for 30 min.tetrakis(triphenylphosphine) palladium(0) was added and degassed forfurther 30 min. Reaction mixture was refluxed for 2 h. After completionof the reaction, work-up (AcOEt/H₂O) followed by column afforded1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole(85 mg) as a white solid. The title compound (26 mg) was prepared from4-bromo-2,6-difluoroaniline (50 mg, 0.24 mmol) and1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole(85 mg, 0.31 mmol) as a white solid. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz):7.93 (s, 1H), 7.66 (dd, J 1.5, 8.8, 1H), 7.55 (d, J 8.8, 1H), 7.33 (dd,J 2, 8.2, 2H), 5.22 (s, 2H), 3.94 (s, 3H), 2.49 (s, 3H).

Intermediate 46: 3′-chloro-3,5-difluoro-5′-methoxybiphenyl-4-amine

The title compound (39 mg) was prepared from 4-bromo-2,6-difluoroaniline(100 mg, 0.48 mmol) and 3-chloro-5-methoxyphenylboronic acid (116 mg,0.62 mmol) as a pale-yellow solid. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz):7.36 (dd, J 2.2, 8.1, 2H), 7.25 (s, 1H), 7.12 (s, 1H), 6.91 (t, J 1.9,1H), 5.43 (s, 2H), 3.81 (s, 3H).

Intermediate 47: 3-chloro-5-fluoro-3′,4′-dimethoxybiphenyl-4-amine

The title compound (39 mg) was prepared from4-bromo-2-chloro-6-fluoroaniline (100 mg, 0.442 mmol) and3,4-dimethoxyphenylboronic acid (80 mg, 0.62 mmol) as a pale-yellowsolid.

Intermediate 48: 2′,3-dichloro-5-fluoro-5′-methoxybiphenyl-4-amine

The title compound (39 mg) was prepared from4-bromo-2-chloro-6-fluoroaniline (100 mg, 0.44 mmol) and2-chloro-5-methoxyphenylboronic acid (106 mg, 0.62 mmol) as apale-yellow solid.

Intermediate 49: 2′,3,5-trifluoro-5′-methoxybiphenyl-4-amine

The title compound (31 mg) was prepared from 4-bromo-2,6-difluoroaniline(100 mg, 0.48 mmol) and 2-fluoro-5-methoxyphenylboronic acid (106 mg,0.62 mmol) as a pale-yellow solid.

Intermediate 50: 4′-chloro-3,5-difluoro-3′-methoxybiphenyl-4-amine

The title compound (81 mg) was prepared from 4-bromo-2,6-difluoroaniline(100 mg, 0.48 mmol) and 4-chloro-5-methoxyphenylboronic acid (116 mg,0.62 mmol) as a white solid.

Intermediate 51: 3,4′-dichloro-5-fluoro-3′-methoxybiphenyl-4-amine

The title compound (82 mg) was prepared from4-bromo-2-chloro-6-fluoroaniline (100 mg, 0.44 mmol) and4-chloro-5-methoxyphenylboronic acid (107 mg, 0.62 mmol) as apale-yellow solid.

Intermediate 52: 3-chloro-2′,5-difluoro-5′-methoxybiphenyl-4-amine

The title compound (70 mg) was prepared from4-bromo-2-chloro-6-fluoroaniline (100 mg, 0.44 mmol) and2-fluoro-5-methoxyphenylboronic acid (98 mg, 0.58 mmol) as a whitesolid. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 7.30-7.24 (m, 2H), 7.17 (t, J9.1, 1H), 7.02-6.97 (m, 1H), 6.90-6.84 (m, 1H), 5.61 (s, 2H), 3.77 (s,3H).

Intermediate 53: 3,4′,5-trifluoro-3′-methoxybiphenyl-4-amine

The title compound (480 mg) was prepared from4-bromo-2,6-difluoroaniline (200 mg, 0.96 mmol) and4-fluoro-5-methoxyphenylboronic acid (210 mg, 1.24 mmol) as a whitesolid. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 7.39-7.29 (m, 3H), 7.21-7.12(m, 2H), 5.33 (s, 2H), 3.90 (s, 3H).

Intermediate 54: 2,6-difluoro-4-(3-methyl-1H-indol-5-yl)aniline

The title compound (68 mg) was prepared from 4-bromo-2,6-difluoroaniline(100 mg, 0.48 mmol) and3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (160mg, 0.62 mmol) as a white solid. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 10.71(s, 1H), 7.67 (s, 1H), 7.33-7.29 (m, 2H), 7.28-7.21 (m, 2H), 7.09 (s,1H), 5.12 (s, 2H), 2.27 (s, 3H).

Intermediate 55: 2,6-difluoro-4-(3-methyl-1H-indazol-5-yl)aniline

Following the general procedure-1, tert-butyl5-(4-amino-3,5-difluorophenyl)-3-methyl-1H-indazole-1-carboxylate (106mg) was prepared from 4-bromo-2,6-difluoroaniline (250 mg, 1.2 mmol) andteRT-butyl3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-1-carboxylate(559 mg, 1.56 mmol) as a white solid. teRT-butyl5-(4-amino-3,5-difluorophenyl)-3-methyl-1H-indazole-1-carboxylate (205mg) was dissolved in dichloromethane (4 ml), trifluoroacetic acid (0.8ml) was added and stirred at RT for 4 h. The solvent was removed and theresidue co-evaporated 4 times with dihloromethane. Solid obtained wasdried under high vacuum to obtain the title compound (243 mg) as a whitesolid. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 9.01 (bs, 1H), 7.92 (s, 1H),7.58 (dd, J 1.4, 8.7, 1H), 7.44 (d, J 8.7, 1H), 7.32 (dd, J 2, 8.2, 2H),5.22 (s, 2H), 2.50 (s, 3H).

Intermediate 56: 3-chloro-3′-ethyl-5-fluorobiphenyl-4-amine

The title compound (83 mg) was prepared from 4-bromo-2,6-difluoroaniline(100 mg, 0.48 mmol) and 3-ethylphenylboronic acid (86 mg, 0.57 mmol) asa yellow liquid.

Intermediate 57: 3-chloro-3′-ethoxy-2′,5-difluorobiphenyl-4-amine

The title compound (65 mg) was prepared from4-bromo-2-chloro-6-fluoroaniline (120 mg, 0.53 mmol) and3-ethoxy-2-fluorophenylboronic acid (120 mg, 0.69 mmol) as a colourlessliquid.

Intermediate 58:2-chloro-4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-fluoroaniline

The title compound (68 mg) was prepared from 4-bromo-2,6-difluoroaniline(100 mg, 0.48 mmol) and 2,3-dihydrobenzo[b][1,4]dioxin-6-ylboronic acid(160 mg, 0.62 mmol) as a white solid.

Intermediate 59:3-chloro-5-fluoro-3′-(2,2,2-trifluoroethoxy)biphenyl-4-amine

The title compound (85 mg) was prepared from4-bromo-2-chloro-6-fluoroaniline (100 mg, 0.44 mmol) and3-(2,2,2-trifluoroethoxy)phenylboronic acid (127 mg, 0.57 mmol) as awhite solid. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 7.53-7.44 (m, 2H),7.38-7.26 (m, 3H), 6.94 (d, J 7, 1H), 5.55 (s, 2H), 4.83 (q, J 8.9, 2H).

Intermediate 60: 3-fluoro-3′-methoxybiphenyl-4-amine

The title compound (430 mg) was prepared from 4-bromo-6-fluoroaniline(500 mg, 2.63 mmol) and 3-Methoxyphenylboronic acid (519 mg, 3.42 mmol)as a red liquid. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 7.34 (dd, J 2, 13.1,1H), 7.27 (t, J 7.9, 1H), 7.22 (dd, J 2, 8.3, 1H), 7.12 (d, J 7.9, 1H),7.09-7.07 (m, 1H), 6.84-6.78 (m, 2H), 5.29 (s, 2H), 3.78 (s, 3H).

Intermediate 61: 3′-ethoxybiphenyl-4-amine

The title compound (200 mg) was prepared from 4-bromoaniline (300 mg,1.74 mmol) and 3-ethoxyphenylboronic acid (380 mg, 2.29 mmol) as acolourless liquid. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 7.33 (d, J 8.5,2H), 7.26-7.22 (m, 1H), 7.06 (d, J 7.9, 1H), 7.01 (s, 1H), 6.75 (dd, J5.8, 8.1, 1H), 6.60 (d, J 8.5, 2H), 5.20 (s, 2H), 4.04 (q, J 7, 2H),1.16 (t, J 7, 3H).

Intermediate 62: 3′-(ethylthio)-3,5-difluorobiphenyl-4-amine

The title compound (900 mg) was prepared from4-bromo-2,6-difluoroaniline (1 g, 4.8 mmol) and3-(ethylthio)phenylboronic acid (1.13 g, 6.24 mmol) as a colourlessliquid.

Intermediate 63: 3′-cyclopropoxy-3,5-difluorobiphenyl-4-amine

The title compound (170 mg) was prepared from4-bromo-2,6-difluoroaniline (1.2 g, 5.76 mmol) and2-(3-cyclopropoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.5 g,5.76 mmol) as a yellow liquid.

Intermediate 64:3-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole

5-Bromoisatin (5 g, 22.12 mmol) was added drop-wise to ethyl magnesiumiodide formed from ethyl iodide (14 ml, 176.96 mmol) and magnesium (8.6g, 176.96 mmol) in Et₂O (50 ml) and stirred at RT overnight. Work-up(EtOAc/H₂O) after adding aq. 10% NH₄Cl solution and purification gave5-bromo-3-ethyl-3-hydroxyindolin-2-one (1 g). To a solution of thisintermediate (1 g, 3.93 mmol) in THF (40 ml) was added a 2M solutionborane-dimethyl sulphide in THF (10 ml, 19.65 mmol) and stirred at RTfor 3 h. Work up (EtOAc/H₂O) and purification using afforded5-Bromo-3-ethyl indole (800 mg). To a solution of 5-Bromo-3-ethyl indole(800 mg, 3.57 mmol) in dioxane (10 ml) were added bis(pinacolato)diboron(1.078 g, 4.64 mmol), potassium acetate (1.15 g, 11.78 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂,degassed for 30 min. and refluxed overnight. Work-up followed bypurification afforded title compound (800 mg) as an off-white solid.

Intermediate 65: 4-(3-ethyl-1H-indol-5-yl)-2,6-difluoroaniline

The title compound (220 mg) was prepared from4-bromo-2,6-difluoroaniline (662 mg, 2.57 mmol) and intermediate 64 (440mg, 1.78 mmol) as a yellow liquid. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz):10.74 (s, 1H), 7.69 (s, 1H), 7.33-7.29 (m, 2H), 7.23 (dd, J 1.8, 8.3,2H), 7.09 (s, 1H), 5.12 (s, 2H), 2.73 (q, J 7.5, 2H), 1.27 (q, J 7.5,3H).

Intermediate 66: 3′-(ethylthio)-2,3,5,6-tetrafluorobiphenyl-4-amine

The title compound (280 mg) was prepared from4-bromo-2,3,5,6-tetrafluoroaniline (300 mg, 1.22 mmol) and3-(ethylthio)phenylboronic acid (291 mg, 1.6 mmol) as a colourlessliquid.

Intermediate 67: 2′-chloro-2-fluoro-5′-methoxybiphenyl-4-amine

The title compound (280 mg) was prepared from 4-bromo-3-fluoroaniline(227 mg, 1.2 mmol) and 2-chloro-5-methoxyphenylboronic acid (290 mg, 1.6mmol) as a pale-yellow liquid.

Intermediate 68: 3-fluoro-3′-propoxybiphenyl-4-amine

The title compound (280 mg) was prepared from 4-bromo-2-fluoroaniline(390 mg, 1.6 mmol) and 3-propoxyphenylboronic acid (369 mg, 2 mmol) as acolourless liquid.

Intermediate 69: 3′-propoxybiphenyl-4-amine

The title compound (280 mg) was prepared from 4-bromoaniline (300 mg,1.7 mmol) and 3-propoxyphenylboronic acid (408 mg, 2.3 mmol) as acolourless liquid.

Intermediate 70: 3′-(ethylthio)-2-fluorobiphenyl-4-amine

The title compound (430 mg) was prepared from 4-bromo-3-fluoroaniline(300 mg, 1.6 mmol) and 3-(ethylthio)phenylboronic acid (370 mg, 2.0mmol) as a yellow liquid.

Intermediate 71: 3,5-difluoro-3′-(2,2,2-trifluoroethoxy)biphenyl-4-amine

The title compound (89 mg) was prepared from 4-bromo-2,6-difluoroaniline(80 mg, 0.38 mmol) and 3-(2,2,2-trifluoroethoxy)phenylboronic acid (108mg, 0.5 mmol) as a colourless liquid.

Intermediate 72: 3′-ethyl-3,5-difluorobiphenyl-4-amine

The title compound (89 mg) was prepared from 4-bromo-2,6-difluoroaniline(100 mg, 0.48 mmol) and 3-ethylphenylboronic acid (99 mg, 0.6 mmol) as acolourless liquid.

Intermediate 73: 2′-chlorobiphenyl-4-amine

The title compound (176 mg) was prepared from 4-bromoaniline (300 mg,1.74 mmol) and 2-chlorophenylboronic acid (354 mg, 2.26 mmol) as ayellow solid.

Intermediate 74: 3′-methoxybiphenyl-4-amine

The title compound (58 mg) was prepared from 4-bromoaniline (300 mg,1.74 mmol) and 3-methoxyphenylboronic acid (344 mg, 2.26 mmol) as ayellow liquid.

Intermediate 75: 3′-(trifluoromethoxy)biphenyl-4-amine

The title compound (280 mg) was prepared from 4-bromoaniline (300 mg,1.74 mmol) and 3-(trifluoromethoxy)phenylboronic acid (466 mg, 2.26mmol) as a pale-yellow liquid.

Intermediate 76: 3′-(ethylthio)-2,6-difluorobiphenyl-4-amine

The title compound (500 mg) was prepared from4-bromo-3,5-difluoroaniline (300 mg, 1.74 mmol) and3-(ethylthio)phenylboronic acid (340 mg, 1.86 mmol) as a yellow liquid.

Intermediate 77: 3′-ethylbiphenyl-4-amine

The title compound (300 mg) was prepared from 4-bromoaniline (270 mg,1.56 mmol) and 3-ethylphenylboronic acid (300 mg, 2.04 mmol) as acolourless liquid.

Intermediate 78: 3′-butoxy-2,3,5,6-tetrafluorobiphenyl-4-amine

The title compound (250 mg) was prepared from4-bromo-2,3,5,6-tetrafluoroaniline (300 mg, 1.23 mmol) and3-butoxyphenylboronic acid (310 mg, 1.59 mmol) as a yellow liquid.

Intermediate 79: 3′-butoxy-3-fluorobiphenyl-4-amine

The title compound (170 mg) was prepared from 4-bromo-2-fluoroaniline(240 mg, 1.26 mmol) and 3-butoxyphenylboronic acid (310 mg, 1.59 mmol)as a yellow liquid.

Intermediate 80: 3′-cyclopropoxy-3-fluorobiphenyl-4-amine

The title compound (230 mg) was prepared from 4-bromo-2-fluoroaniline (1g, 5.26 mmol) and 3-isopropoxyphenylboronic acid (1.8 g, 6.84 mmol) as ayellow liquid.

Intermediate 81: 3′-cyclopropoxybiphenyl-4-amine

The title compound (98 mg) was prepared from 4-bromoaniline (1 g, 5.81mmol) and 3-isopropoxyphenylboronic acid (1.96 g, 7.55 mmol) as a yellowliquid.

Intermediate 82: 3′-butoxy-3-fluorobiphenyl-4-amine

The title compound (84 mg) was prepared from 4-bromoaniline (200 mg,1.16 mmol) and 3-butoxyphenylboronic acid (293 mg, 1.5 mmol) as a yellowliquid.

Intermediate 83: 3′-butoxy-2-fluorobiphenyl-4-amine

The title compound (241 mg) was prepared from 4-bromo-3-fluoroaniline(200 mg, 1.05 mmol) and 3-butoxyphenylboronic acid (265 mg, 1.4 mmol) asa colourless liquid.

Intermediate 84: 3′-butoxy-2,6-difluorobiphenyl-4-amine

The title compound (172 mg) was prepared from4-bromo-3,5-difluoroaniline (200 mg, 1 mmol) and 3-butoxyphenyl boronicacid (242 mg, 1.2 mmol) as a colourless liquid.

Intermediate 85:3-propyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole

The title compound (500 mg) was prepared as a colourless viscous liquidby using the procedure followed for intermediate 64 from propylmagnesium bromide generated from propyl bromide (16.2 ml, 176.96 mmol)and magnesium (4.3 g, 176.96 mmol) in ether (50 ml), 5-bromoisatin (5 g,22.12 mmol), THF (20 ml), 2M borane-dimethyl sulphide in THF (10 ml,19.65 mmol), bis(pinacolato)diboron (600 mg, 2.3 mmol), potassiumacetate (600 mg, 2.3 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂ (44mg, 0.03 mmol) and dioxane (10 ml).

Intermediate 86: 2,6-difluoro-4-(3-propyl-1H-indol-5-yl)aniline

The title compound (240 mg) was prepared from4-bromo-2,6-difluoroaniline (400 mg, 1.55 mmol) and intermediate 85 (500mg, 2.11 mmol) as a colourless gummy liquid.

Intermediate 87: 2-chloro-4-(3-ethyl-1H-indol-5-yl)-6-fluoroaniline

The title compound (60 mg) was prepared from4-bromo-2-chloro-6-fluoroaniline (300 mg, 1.1 mmol) and intermediate 64(316 mg, 1.42 mmol) as a brown viscous liquid.

Intermediate 88: 2′-chloro-3-fluoro-5′-methoxybiphenyl-4-amine

The title compound (134 mg) was prepared from 4-bromo-2-fluoroaniline(150 mg, 0.79 mmol) and 2-chloro-5-methoxylphenylboronic acid (191 mg,1.02 mmol) as a colourless liquid.

Intermediate 89: 2′-chloro-5′-methoxybiphenyl-4-amine

The title compound (154 mg) was prepared from 4-bromoaniline (150 mg,0.87 mmol) and 2-chloro-5-methoxyphenyl boronic acid (211 mg, 1.13 mmol)as a colourless viscous liquid.

General Procedure for Amide Formation:

Procedure-1

A solution of an anhydride (1.3 eq.) and an amine (1 eq) were dissolvedin dioxane and refluxed overnight. Dioxane was evaporated and theresultant residue dissolved in AcOEt and extracted into aq. 2N NaHCO₃solution. The aqueous layer was acidified with aq. 2N HCl to obtain asolid, which was filtered and dried to give the desired amide.

Examples 1-11, 14, 16-17 and 20 were synthesised using generalprocedure-1.

Procedure-2

An amine (1 eq) was dissolved in toluene and an anhydride (1 eq) wasadded in portions and the mixture heated to 60° C. for 4 h. Solidifiedproduct was filtered and washed with aq. 2N HCl and dried under vacuumto obtain the desired product.

Examples 12 and 13 were synthesised using general procedure-2.

Procedure-3

An amine (1 eq) was dissolved in acetic acid and an anhydride (2 eq) wasadded and the mixture stirred at RT overnight. The solid that separatedout was filtered and washed with petroleum ether and dried under vacuumto obtain the desired product.

Examples 15, 18, 19, 21-35, 38-71 and 73-100 were prepared using generalprocedure-3.

Example 1 2-(3,5-Difluoro-3′-methoxybiphenyl-4-ylcarbamoyl)benzoic acid

The title compound (52 mg) was obtained from intermediate 1 (150 mg,0.64 mmol) and phthalic anhydride (189 mg) as a white solid. M.P.:168-173° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.05 (s, 1H), 10.19 (s,1H), 7.83 (d, J 7.4, 1H), 7.69-7.63 (m, 1H), 7.62-7.52 (m, 4H), 7.39 (t,J 7.9, 1H), 7.34-7.27 (m, 2H), 6.98 (d, J 6.8, 1H), 3.83 (s, 3H). MS(m/z): 381.55 ([M−H]⁻).

Example 22-(3,5-Difluoro-3′-methoxybiphenyl-4-ylcarbamoyl)benzenesulfonic acid

The title compound (64 mg) was obtained from intermediate 1 (150 mg,0.64 mmol) and 2-sulphobenzoic acid cyclic anhydride (235 mg) as a brownsolid. M.P.: 97-102° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 11.48 (s, 1H),7.92 (d, J 7.1, 1H), 7.80 (d, J 7, 1H), 7.57-7.49 (m, 4H), 7.38 (t, J7.8, 1H), 7.34-7.28 (m, 2H), 6.97 (d, J 8.1, 1H), 3.83 (s, 3H). MS(m/z): 417.6 ([M−H]⁻).

Example 3 2-(6-(3-Methoxyphenyl)pyridin-3-ylcarbamoyl)benzoic acid

The title compound (48 mg) was obtained from intermediate 3 (100 mg, 0.5mmol) and phthalic anhydride (147 mg, 1 mmol) as a white solid. M.P.:194-199° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.17 (bs, 1H), 10.64 (s,1H), 8.88 (d, J 2, 1H), 8.22 (dd, J 2.2, 8.7, 1H), 7.97 (d, J 8.7, 1H),7.90 (d, J 7, 1H), 7.70-7.66 (m, 1H), 7.63-7.56 (m, 4H), 7.38 (t, J 8,1H), 6.98-6.95 (m, 1H), 3.82 (s, 3H). MS (m/z): 347.30 ([M−H]⁻).

Example 4 2-(3′-Ethoxy-3-fluorobiphenyl-4-ylcarbamoyl)benzoic acid

The title compound (26 mg) was obtained from intermediate 4 (100 mg, 0.5mmol) and phthalic anhydride (128 mg, 1 mmol) as a white solid. M.P.:151-157° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.06 (s, 1H), 10.22 (s,1H), 7.95 (t, J 8.5, 1H), 7.89 (d, J 7.7, 1H), 7.68-7.52 (m, 5H), 7.35(t, J 7.9, 1H), 7.25 (d, J 8.2, 1H), 7.21 (s, 1H), 6.92 (d, J 8.4, 1H),4.10 (q, J 7, 2H), 1.34 (t, J 7, 3H). MS (m/z): 379.24 ([M]⁻).

Example 5 2-(3′-Ethoxy-3,5-difluorobiphenyl-4-ylcarbamoyl)benzoic acid

The title compound (15 mg) was obtained from intermediate 5 (100 mg,0.43 mmol) and pthalic anhydride (118 mg, 0.86 mmol) as a white solid.M.P.: 136-141° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.04 (s, 1H), 10.19(s, 1H), 7.83 (d, J 7.4, 1H), 7.69-7.64 (m, 1H), 7.62-7.51 (m, 4H), 7.37(t, J 7.9, 1H), 7.32-7.25 (m, 2H), 6.96 (dd, J 1.7, 8.3, 1H), 4.11 (q, J7, 2H), 1.34 (t, J 7, 3H). MS (m/z): 395.81 ([M−H]⁻).

Example 63-(3,5-Difluoro-3′-methoxybiphenyl-4-ylcarbamoyl)pyrazine-2-carboxylicacid

The title compound (270 mg) was obtained from intermediate 1 (150 mg,0.64 mmol) and 2,3-pyrazinedicarboxylic anhydride (190 mg, 1.26 mmol) asa white solid. M.P.: 180.1-183.4° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz):13.82 (bs, 1H), 10.7 (s, 1H), 8.92 (d, J 5.7, 2H), 7.59 (d, J 9.1, 2H),7.42-7.38 (m, 1H), 7.36-7.28 (m, 2H), 7.00 (d, J 8, 1H), 3.83 (s, 3H).MS (m/z): 384.05 ([M−H]⁻).

Example 73-(3,5-Difluoro-3′-ethoxybiphenyl-4-ylcarbamoyl)pyrazine-2-carboxylicacid

The title compound (84 mg) was obtained from intermediate 5 (100 mg, 0.4mmol) and 2,3-pyrazinedicarboxylic anhydride (120 mg, 0.8 mmol) as awhite solid. M.P.: 133.4-137.3° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz):13.76 (s, 1H), 10.68 (s, 1H), 8.92 (dd, J 2.3, 7.7, 2H), 7.58 (d, J 9.2,2H), 7.41-7.36 (m, 1H), 7.34-7.26 (m, 2H), 6.98 (d, J 8, 1H), 4.11 (q, J6.9, 2H), 1.35 (t, J 6.9, 3H). MS (m/z): 398.19 ([M−H]⁻).

Example 8 2-(2′-Chloro-3,5-difluorobiphenyl-4-ylcarbamoyl)benzoic acid

The title compound (110 mg) was obtained from intermediate 6 (140 mg,0.59 mmol) and phthalic anhydride (170 mg, 1.17 mmol) as a white solid.M.P.: 143.5-145.1° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.06 (s, 1H),10.2 (s, 1H), 7.85 (d, J 7.6, 1H), 7.67 (t, J 7.3, 1H), 7.63-7.56 (m,3H), 7.52-7.43 (m, 3H), 7.28 (d, J 8.4, 2H). MS (m/z): 386.15 ([M−H]⁻).

Example 93-[3′-(Benzyloxy)-3,5-difluorobiphenyl-4-ylcarbamoyl]pyrazine-2-carboxylicacid

The title compound (42 mg) was obtained from intermediate 9 (65 mg, 0.21mmol) and 2,3-Pyrazinedicarboxylic anhydride (62 mg, 0.42 mmol) as awhite solid. M.P.: 142-144.5° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.77(bs, 1H), 10.69 (s, 1H), 8.92 (dd, J 2.4, 7.7, 2H), 7.60 (d, J 9.2, 2H),7.48 (d, J 7.3, 2H), 7.44-7.32 (m, 6H), 7.07 (d, J 6.5, 1H), 5.20 (s,2H). MS (m/z): 460.28 ([M−H]⁻).

Example 10 2-(3,5-Difluorobiphenyl-4-ylcarbamoyl)benzoic acid

The title compound (85 mg) was obtained from intermediate 7 (100 mg,0.48 mmol) and phthalic anhydride (144 mg, 0.86 mmol) as a white solid.M.P.: 161.2-165.7° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.04 (s, 1H),10.19 (s, 1H), 7.83 (d, J 7.6, 1H), 7.76 (d, J 7.4, 2H), 7.65 (d, J 8.2,1H), 7.62-7.48 (m, 6H), 7.43 (d, J 7.2, 1H). MS (m/z): 352.06 ([M−H]⁻).

Example 113-(3-Chloro-3′-ethoxy-5-fluorobiphenyl-4-ylcarbamoyl)pyrazine-2-carboxylicacid

The title compound (30 mg) was obtained from intermediate 10 (100 mg,0.38 mmol) and 2,3-pyrazinedicarboxylic anhydride (112 mg, 0.75 mmol) asa white solid. M.P.: 148-153° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.74(bs, 1H), 10.72 (s, 1H), 8.93 (dd, J 2.3, 6.4, 2H), 7.76 (s, 1H), 7.70(d, J 10.7, 1H), 7.42-7.36 (m, 1H), 7.34-7.26 (m, 2H), 6.98 (dd, J 1.8,8.1, 1H), 4.12 (q, J 6.9, 2H), 1.34 (t, J 6.9, 3H). MS (m/z): 414.01([M−H]⁻).

Example 122-[3,5-Difluoro-3′-(trifluoromethoxy)biphenyl-4-ylcarbamoyl]benzoic acid

The title compound (15 mg) was obtained from intermediate 8 (100 mg,0.34 mmol) and phthalic anhydride (50 mg, 0.34 mmol) as a white solid.M.P.: 148.2-151.4° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.07 (s, 1H),10.24 (s, 1H), 7.83 (t, J 6.2, 2H), 7.79 (s, 1H), 7.54-7.50 (m, 6H),7.42 (d, J 8.8, 1H). MS (m/z): 436.13 ([M−H]⁻).

Example 13 2-[3′-(Benzyloxy)-3,5-difluorobiphenyl-4-ylcarbamoyl]benzoicacid

The title compound (12 mg) was obtained from intermediate 9 (100 mg,0.32 mmol) and phthalic anhydride (47 mg, 0.32 mmol) as a white solid.M.P.: 140.3-143.4° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.04 (s, 1H),10.19 (s, 1H), 7.83 (d, J 7.6, 1H), 7.68-7.64 (m, 1H), 7.62-7.53 (m,4H), 7.48 (d, J 7.2, 2H), 7.42-7.37 (m, 4H), 7.36-7.32 (m, 2H), 7.05(dd, J 2, 7.7, 1H), 5.20 (s, 2H). MS (m/z): 457.83 ([M−H]⁻).

Example 144,5-Dichloro-2-(3-chloro-3′-ethoxy-5-fluorobiphenyl-4-ylcarbamoyl)benzoicacid

The title compound (42 mg) was obtained from intermediate 10 (100 mg,0.38 mmol) and phthalic anhydride (160 mg, 0.75 mmol) as an off-whitesolid. M.P.: 260-265° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 15.33 (s,1H), 8.16 (s, 1H), 7.96 (s, 1H), 7.71 (s, 1H), 7.64 (d, J 11, 1H), 7.36(t, J 7.8, 1H), 7.27-7.22 (m, 2H), 6.95 (dd, J 1.8, 8.1, 1H), 4.12 (d, J7, 2H), 1.34 (t, J 7, 3H). MS (m/z): 481.02 ([M−H]⁻).

Example 15 2-(3-Chloro-3′-ethoxy-5-fluorobiphenyl-4-ylcarbamoyl)benzoicacid

The title compound (86 mg) was obtained from intermediate 10 (145 mg,0.55 mmol) and phthalic anhydride (160 mg, 1.1 mmol) as a white solid.M.P.: 135-140° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.02 (s, 1H), 10.23(s, 1H), 7.82 (d, J 7.6, 1H), 7.72 (s, 1H), 7.70-7.58 (m, 4H), 7.38 (t,J 7.8, 1H), 7.33-7.26 (m, 2H), 6.97 (dd, J 2, 8.1, 1H), 4.12 (q, J 6.9,2H), 1.35 (t, J 6.9, 3H). MS (m/z): 412.05 ([M−H]⁻).

Example 164,5-Dichloro-2-(3,5-difluoro-3′-methoxybiphenyl-4-ylcarbamoyl)benzoicacid

The title compound (95 mg) was obtained from intermediate 1 (100 mg,0.42 mmol) and 5,6-dichloroisobenzofuran-1,3-dione (182 mg, 0.84 mmol)as a white solid. M.P.: 158.6-162.2° C. ¹H-NMR (δ ppm, DMSO-d₆, 400MHz): 13.58 (s, 1H), 10.40 (s, 1H), 7.57 (d, J 9.1, 2H), 8.03 (s, 1H),7.83 (s, 1H), 7.39 (t, J 7.9, 1H), 7.34-7.28 (m, 2H), 6.98 (dd, J 1.9,6.9, 1H), 3.83 (s, 3H). MS (m/z): 451.24 ([M−H]⁻).

Example 174,5-Dichloro-2-(3′-ethoxy-3,5-difluorobiphenyl-4-ylcarbamoyl)benzoicacid

The title compound (87 mg) was obtained from intermediate 5 (100 mg,0.42 mmol) and 5,6-dichloroisobenzofuran-1,3-dione (173 mg, 0.8 mmol) asa white solid. M.P.: 190.1-192.4° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz):13.58 (s, 1H), 10.39 (s, 1H), 8.03 (s, 1H), 7.82 (s, 1H), 7.56 (d, J9.2, 2H), 7.37 (t, J 7.9, 1H), 7.33-7.26 (m, 2H), 6.97 (dd, J 1.8, 8.1,1H), 4.11 (q, J 7, 2H), 1.34 (t, J 7, 3H). MS (m/z): 464.92 ([M−H]⁻).

Example 18 2-(3,5-Dichloro-3′-methoxybiphenyl-4-ylcarbamoyl)benzoic acid

The title compound (20 mg) was obtained from intermediate 11 (150 mg,0.56 mmol) and phthalic anhydride (165 mg, 1.12 mmol) as a white solid.M.P.: 163-168° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.0 (s, 1H), 10.37(s, 1H), 7.86 (s, 2H), 7.80 (d, J 7.5, 1H), 7.74-7.65 (m, 2H), 7.60 (t,J 7.5, 1H), 7.40 (t, J 7.9, 1H), 7.34-7.27 (m, 2H), 6.99 (d, J 7.5, 1H),3.84 (s, 3H). MS (m/z): 415.15 ([M−H]⁻).

Example 19 2-(3-Chloro-5-fluoro-3′-propoxybiphenyl-4-ylcarbamoyl)benzoicacid

The title compound (38 mg) was obtained from intermediate 12 (100 mg,0.36 mmol) and phthalic anhydride (105 mg, 0.72 mmol) as a white solid.M.P.: 144-148° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.03 (s, 1H), 10.24(s, 1H), 7.82 (d, J 7.5, 1H), 7.73 (s, 1H), 7.70-7.57 (m, 4H), 7.38 (t,J 7.7, 1H), 7.32-7.26 (m, 2H), 6.98 (d, J 8.1, 1H), 4.02 (t, J 6.5, 2H),1.77-1.72 (m, 2H), 0.99 (t, J 7.4, 3H). MS (m/z): 426.05 ([M−H]⁻).

Example 20 2-(3-Chloro-2′,5-difluorobiphenyl-4-ylcarbamoyl)benzoic acid

The title compound (15 mg) was obtained from intermediate 13 (100 mg,0.34 mmol) and phthalic anhydride (100 mg, 0.68 mmol) as a white solid.M.P.: 163-167° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.05 (s, 1H), 10.3(s, 1H), 7.83 (d, J 7.6, 1H), 7.70-7.58 (m, 5H), 7.57-7.46 (m, 2H),7.40-7.31 (m, 2H). MS (m/z): 386.15 ([M−H]⁻).

Example 21 2-(3,5-Dichloro-3′-ethoxybiphenyl-4-ylcarbamoyl)benzoic acid

The title compound (30 mg) was obtained from intermediate 14 (150 mg,0.53 mmol) and phthalic anhydride (157 mg, 1.06 mmol) as a white solid.M.P.: 135.9-138.2° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.0 (s, 1H),10.37 (s, 1H), 7.86 (s, 2H), 7.80 (d, J 7.3, 1H), 7.74-7.64 (m, 2H),7.62-7.55 (m, 1H), 7.38 (t, J 7.9, 1H), 7.32-7.26 (m, 2H), 7.00-6.96 (m,1H), 4.12 (q, J 7, 2H), 1.34 (t, J 7, 3H). MS (m/z): 429.30 ([M−H]⁻).

Example 222-[3-Fluoro-3′-(trifluoromethoxy)biphenyl-4-ylcarbamoyl]benzoic acid

The title compound (124 mg) was obtained from intermediate 15 (100 mg,0.44 mmol) and phthalic anhydride (130 mg, 0.9 mmol) as a white solid.M.P.: 128.3-132.1° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.07 (s, 1H),10.28 (s, 1H), 7.99 (t, J 8.3, 1H), 7.88 (d, J 7.4, 1H), 7.77 (d, J 8,1H), 7.67 (s, 1H), 7.69-7.52 (m, 6H), 7.37 (d, J 8.2, 1H). MS (m/z):417.86 ([M−H]⁻).

Example 232-[2′-Fluoro-3-(trifluoromethoxy)biphenyl-4-ylcarbamoyl]benzoic acid

The title compound (82 mg) was obtained from intermediate 16 (100 mg,0.36 mmol) and phthalic anhydride (109 mg, 0.72 mmol) as a white solid.M.P.: 142.2-148.1° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.08 (s, 1H),10.36 (s, 1H), 8.03 (d, J 8.2, 1H), 7.90 (d, J 7.8, 1H), 7.68 (t, J 7.5,1H), 7.65-7.54 (m, 4H), 7.49-7.41 (m, 2H), 7.38-7.30 (m, 2H). MS (m/z):418.00 ([M−H]⁻).

Example 24 2-(3,5-Dichloro-2′-fluorobiphenyl-4-ylcarbamoyl)benzoic acid

The title compound (78 mg) was obtained from intermediate 17 (100 mg,0.39 mmol) and phthalic anhydride (115 mg, 0.78 mmol) as a white solid.M.P.: 185.4-193.6° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.02 (s, 1H),10.42 (s, 1H), 7.81 (d, J 7.4, 1H), 7.74 (s, 2H), 7.72-7.58 (m, 4H),7.53-7.47 (m, 1H), 7.40-7.31 (m, 2H). MS (m/z): 402.11 ([M−H]⁻).

Example 25 2-(3,5-Difluoro-3′-isopropoxybiphenyl-4-ylcarbamoyl)benzoicacid

The title compound (64 mg) was obtained from intermediate 18 (100 mg,0.38 mmol) and phthalic anhydride (112 mg, 0.76 mmol) as a white solid.M.P.: 122-125° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.05 (s, 1H), 10.20(s, 1H), 7.83 (d, J 7.5, 1H), 7.66 (t, J 7.3, 1H), 7.60-7.52 (m, 4H),7.37 (t, J 7.8, 1H), 7.30-7.24 (m, 2H), 6.96 (dd, J 2.1, 8.2, 1H), 4.76(septet, J 6.0, 1H), 1.28 (d, J 6, 6H). MS (m/z): 410.02 ([M−H]⁻).

Example 26 2-(3,5-Difluoro-3′-propoxybiphenyl-4-ylcarbamoyl)benzoic acid

The title compound (68 mg) was obtained from intermediate 19 (100 mg,0.38 mmol) and phthalic anhydride (112 mg, 0.76 mmol) as a white solid.M.P.: 128.6-132.1° C. ¹H-NMR (8 ppm, DMSO-d₆, 400 MHz): 13.05 (s, 1H),10.19 (s, 1H), 7.83 (d, J 7.7, 1H), 7.66 (t, J 7.4, 1H), 7.62-7.52 (m,4H), 7.37 (t, J 7.8, 1H), 7.32-7.26 (m, 2H), 6.97 (dd, J 2, 8.1, 1H),4.01 (t, J 6.5, 2H), 1.77-1.67 (m, 2H), 0.99 (t, J 7.4, 3H). MS (m/z):410.16 ([M−H]⁻).

Example 274,5-Dichloro-2-(2′,3-dichloro-5-fluorobiphenyl-4-ylcarbamoyl)benzoicacid

The title compound (110 mg) was obtained from intermediate 20 (100 mg,0.39 mmol) and 5,6-dichloroisobenzofuran-1,3-dione (169 mg, 0.78 mmol)as a white solid. M.P.: 202.3-206.5° C. ¹H-NMR (δ ppm, DMSO-d₆, 400MHz): 13.60 (s, 1H), 10.50 (s, 1H), 8.04 (s, 1H), 7.82 (s, 1H),7.63-7.58 (m, 1H), 7.52-7.43 (m, 5H). MS (m/z): 471.69 ([M−H]⁻).

Example 283,6-dichloro-2-(3′-ethoxy-3,5-difluorobiphenyl-4-ylcarbamoyl)benzoicacid

The title compound (51 mg) was obtained from intermediate 5 (100 mg, 0.4mmol) and 4,7-dichloroisobenzofuran-1,3-dione (173 mg, 0.8 mmol) as awhite solid. M.P.: 126.9-131.4° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz):13.96 (s, 1H), 10.56 (s, 1H), 7.68 (s, 2H), 7.55 (d, J 9.1, 2H), 7.38(t, J 7.9, 1H), 7.32-7.26 (m, 2H), 6.97 (dd, J 1.7, 12.2, 1H), 4.12 (q,J 7, 2H), 1.34 (t, J 7, 3H).

Example 29 2-(3′-butoxy-3-chloro-5-fluorobiphenyl-4-ylcarbamoyl)benzoicacid

The title compound (39 mg) was obtained from intermediate 21 (90 mg,0.31 mmol) and phthalic anhydride (90 mg, 0.6 mmol) as a white solid.M.P.: 128-130° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.02 (s, 1H), 10.23(s, 1H), 7.82 (d, J 7.9, 1H), 7.73 (s, 1H), 7.60-7.57 (m, 4H), 7.37 (t,J 7.9, 1H), 7.32-7.25 (m, 2H), 6.99-6.96 (m, 1H), 4.06 (t, J 6.4, 2H),1.73-1.68 (m, 2H), 1.45 (h, J 7.5, 2H), 0.94 (t, J 7.4, 3H). MS (m/z):440.19 ([M−H]⁻).

Example 304,5-Dichloro-2-(2′-chloro-3,5-difluorobiphenyl-4-ylcarbamoyl)benzoicacid

The title compound (150 mg) was obtained from intermediate 6 (100 mg,4.18 mmol) and 5,6-dichloroisobenzofuran-1,3-dione (181 mg, 8.4 mmol) asa white solid. M.P.: 202-205.5° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz):13.61 (s, 1H), 10.45 (s, 1H), 8.04 (s, 1H), 7.83 (s, 1H), 7.62-7.58 (m,1H), 7.52-7.49 (m, 1H), 7.48-7.43 (m, 2H), 7.30 (d, J 8.5, 2H). MS(m/z): 455.94 ([M−H]⁻).

Example 312-(3-Chloro-5-fluoro-3′-isobutoxybiphenyl-4-ylcarbamoyl)benzoic acid

The title compound (150 mg) was obtained from intermediate 22 (100 mg,4.18 mmol) and 5,6-dichloroisobenzofuran-1,3-dione (181 mg, 8.4 mmol) asa white solid. M.P.: 202-205.5° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz):13.03 (s, 1H), 10.23 (s, 1H), 7.82 (d, J 7.4, 1H), 7.73 (s, 1H),7.70-7.57 (m, 4H), 7.38 (t, J 7.8, 1H), 7.32-7.26 (m, 2H), 6.99 (dd, J1.7, 8.2, 1H), 3.83 (d, J 6.5, 2H), 2.10-1.99 (m, 1H), 1.00 (d, J 6.7,6H). MS (m/z): 439.84 ([M−H]⁻).

Example 32 2-(2′,3,5-Trifluorobiphenyl-4-ylcarbamoyl)benzoic acid

The title compound (72 mg) was obtained from intermediate 23 (100 mg,0.44 mmol) and phthalic anhydride (130 mg, 0.88 mmol) as a white solid.M.P.: 152.2-156.3° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.06 (s, 1H),10.25 (s, 1H), 7.84 (d, J 7.6, 1H), 7.70-7.56 (m, 4H), 7.52-7.45 (m,1H), 7.43-7.38 (m, 2H), 7.36-7.31 (m, 2H). MS (m/z): 369.91 ([M−H]⁻).

Example 33 2-(2′,3,5-Trichlorobiphenyl-4-ylcarbamoyl)benzoic acid

The title compound (20 mg) was obtained from intermediate 24 (100 mg,0.37 mmol) and phthalic anhydride (130 mg, 0.88 mmol) as a white solid.M.P.: 182-185° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.01 (s, 1H), 10.40(s, 1H), 7.82 (d, J 7.2, 1H), 7.72-7.67 (m, 2H), 7.64-7.59 (m, 4H),7.53-7.50 (m, 1H), 7.49-7.45 (m, 2H). MS (m/z): 419.61 ([M−H]⁻).

Example 34 2-(3,5-Difluoro-3′-isobutoxybiphenyl-4-ylcarbamoyl)benzoicacid

The title compound (34 mg) was obtained from intermediate 25 (100 mg,0.36 mmol) and phthalic anhydride (106 mg, 0.72 mmol) as a white solid.M.P.: 112.6-116.4° C. ¹H-NMR (8 ppm, DMSO-d₆, 400 MHz): 13.04 (s, 1H),10.18 (s, 1H), 7.83 (d, J 7.5, 1H), 7.68-7.64 (m, 1H), 7.62-7.52 (m,4H), 7.37 (t, J 7.8, 1H), 7.33-7.25 (m, 2H), 6.98 (d, J 8.2, 1H), 3.84(d, J 6.5, 2H), 2.10-1.99 (m, 1H), 1.00 (d, J 6.7, 6H). MS (m/z): 423.95([M−H]⁻).

Example 35 2-(3′-Butoxy-3,5-difluorobiphenyl-4-ylcarbamoyl)benzoic acid

The title compound (32 mg) was obtained from intermediate 26 (100 mg,0.36 mmol) and phthalic anhydride (106 mg, 0.72 mmol) as a white solid.M.P.: 119.3-123.3° C. ¹H-NMR (8 ppm, DMSO-d₆, 400 MHz): 13.04 (s, 1H),10.19 (s, 1H), 7.83 (d, J 7.4, 1H), 7.69-7.63 (m, 1H), 7.62-7.52 (m,4H), 7.37 (t, J 7.9, 1H), 7.32-7.26 (m, 2H), 6.97 (dd, J 1.6, 8, 1H),4.05 (t, J 6.4, 2H), 1.72 (q, J 6.4, 2H), 1.47 (h, J 7.5, 2H), 0.94 (t,J 7.3, 3H). MS (m/z): 423.88 ([M−H]⁻).

Example 36N-(3-Chloro-3′-ethoxy-5-fluorobiphenyl-4-yl)-2-(hydroxymethyl)benzamide

Oxalyl chloride (0.86 ml, 9.8 mml) and two drops of DMF were added to asolution of 2-(methoxycarbonyl)benzoic acid (590 mg, 3.27 mmol) indichloromethane (10 ml) and cooled to 0° C. and stirred at RT for 30min. After 30 min., the solvent was removed to obtain methyl2-(chloroformyl)benzoate (quantitative). A solution of this intermediate(401 mg, 2.03 mmol) in dichloromethane was added to a solution ofintermediate 10 (540 mg, 2.03 mmol) and pyridine (0.19 ml, 2.43 mmol) indichloromethane (5 ml) at 0° C. and stirred at RT for 30 min. Work-up(CH₂Cl₂/H₂O) and purification gave methyl2-(3-chloro-3′-ethoxy-5-fluorobiphenyl-4-ylcarbamoyl)benzoate (250 mg)as an off-white solid. Lithium borohydride (20 mg, 0.94 mmol) was addedto a solution of this product (200 mg, 0.47 mmol) in THF (5 ml) at 0° C.and the mixture stirred at RT for 2 hrs. Work-up (EtOAc/aq. 10% NH₄Clthen H₂O) and purification afforded the title compound (30 mg) as awhite solid. M.P.: 139.2-141.5° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz):10.22 (s, 1H), 7.76 (s, 1H), 7.73-7.60 (m, 3H), 7.54 (t, J 6.7, 1H),7.43-7.36 (m, 2H), 7.33-7.26 (m, 2H), 6.97 (dd, J 1.8, 8.1, 1H), 5.32(t, J 5.6, 1H), 4.72 (d, J 5.6, 2H), 4.12 (q, J 7, 2H), 1.35 (t, J 7,3H).

Example 37N-(3′-Ethoxy-3,5-difluorobiphenyl-4-yl)-2-(hydroxymethyl)benzamide

A solution of methyl 2-(chloroformyl)benzoate (prepared as describedunder example 37, 361 mg, 2.0 mmol) in dichloromethane was added slowlyto a solution of intermediate 5 (500 mg, 2.0 mmol) and pyridine (0.19ml, 2.43 mmol) in dichloromethane (5 ml) and stirred at 0° C. andstirred at RT for 30 min. Work-up (CH₂Cl₂/H₂O) and purification gavemethyl 2-(3′-ethoxy-3,5-difluorobiphenyl-4-ylcarbamoyl)benzoate (212 mg)as a pale-yellow solid. Lithium borohydride (21 mg, 0.96 mmol) was addedto a solution of this intermediate (200 mg, 0.48 mmol) in THF (3 ml) at0° C. and the mixture stirred at RT for 2 hrs. work-up (EtOAc/aq. 10%NH₄Cl then H₂O) and purification gave the title compound (21 mg) as awhite solid. M.P.: 94.8-99.1° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 10.16(s, 1H), 7.64 (d, J 7.8, 1H), 7.61-7.51 (m, 4H), 7.42-7.35 (m, 2H),7.32-7.26 (m, 2H), 6.97 (dd, J 2, 7.6, 1H), 5.31 (t, J 5.6, 1H), 4.70(d, J 5.6, 2H), 4.11 (q, J 7, 2H), 1.35 (t, J 7, 3H).

Example 382-(3-Chloro-3′-ethoxy-5-fluorobiphenyl-4-ylcarbamoyl)-6-fluorobenzoicacid

The title compound (20 mg) was obtained from intermediate 10 (100 mg,0.38 mmol) and 4-fluoroisobenzofuran-1,3-dione (125 mg, 0.75 mmol) as awhite solid. M.P.: 156.3-158.2° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz):13.42 (s, 1H), 10.44 (s, 1H), 7.79-7.69 (m, 2H), 7.59-7.50 (m, 3H),7.42-7.34 (m, 1H), 7.32-7.24 (m, 2H), 6.97 (d, J 7.6, 1H), 4.12 (t, J 7,2H), 1.33 (q, J 7, 3H).

Example 392-[3-Chloro-5-fluoro-3′-(trifluoromethoxy)biphenyl-4-ylcarbamoyl]benzoicacid

The title compound (38 mg) was obtained from intermediate 27 (150 mg,0.6 mmol) and phthalic anhydride (176 mg, 1.2 mmol) as a white solid.M.P.: 153-156.5° C. ¹H-NMR (δ ppm, DMSO-d6, 400 MHz): 13.04 (s, 1H),10.28 (s, 1H), 7.87-7.73 (m, 5H), 7.69-7.55 (m, 4H), 7.43 (d, J 7.6,1H). MS (m/z): 451.95 ([M−H]⁻).

Example 40 2-[4-(Benzyloxy)-2,6-difluorophenylcarbamoyl]benzoic acid

The title compound (134 mg) was obtained from intermediate 29 (160 mg,0.65 mmol) and phthalic anhydride (193 mg, 1.3 mmol) as a white solid.M.P.: 176.2-180.6° C. ¹H-NMR (δ ppm, DMSO-d6, 400 MHz): 12.98 (bs, 1H),9.88 (s, 1H), 7.79 (d, J 7.6, 1H), 7.67-7.61 (m, 1H), 7.60-7.52 (m, 2H),7.45 (d, J 7, 2H), 7.40 (t, J 7, 2H), 7.37-7.32 (m, 1H), 6.90 (d, J 9.4,2H), 5.14 (s, 2H).

Example 412-[3′-(Cyclopentyloxy)-3,5-difluorobiphenyl-4-ylcarbamoyl]benzoic acid

The title compound (38 mg) was obtained from intermediate 32 (150 mg,0.6 mmol) and phthalic anhydride (176 mg, 1.2 mmol) as a white solid.M.P.: 153-156.5° C. ¹H-NMR (δ ppm, DMSO-d6, 400 MHz): 13.05 (s, 1H),10.18 (s, 1H), 7.83 (d, J 7.6, 1H), 7.69-7.64 (m, 1H), 7.62-7.49 (m,4H), 7.36 (t, J 8, 1H), 7.30-7.25 (m, 1H), 7.23 (m, 1H), 6.95 (dd, J 2,8.1, 1H), 5.00-4.92 (m, 1H), 2.00-1.90 (m, 2H), 1.76-1.68 (m, 4H),1.64-1.54 (m, 2H). MS (m/z): 436.13 ([M−H]⁻).

Example 422-(3-Chloro-3′-(cyclopentyloxy)-5-fluorobiphenyl-4-ylcarbamoyl)benzoicacid

The title compound (38 mg) was obtained from intermediate 33 (100 mg,0.33 mmol) and phthalic anhydride (96 mg, 0.65 mmol) as a white solid.M.P.: 122-126° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.02 (s, 1H), 10.23(s, 1H), 7.82 (d, J 7.4, 1H), 7.71 (s, 1H), 7.68-7.58 (m, 4H), 7.37 (t,J 7.6, 1H), 7.30-7.21 (m, 2H), 6.95 (dd, J 2.2, 8.1, 1H), 5.00-4.93 (s,1H), 2.00-1.88 (m, 2H), 1.80-1.68 (m, 4H), 1.63-1.54 (m, 2H). MS (m/z):452.16 ([M−H]⁻).

Example 432-[3′-(Difluoromethoxy)-3,5-difluorobiphenyl-4-ylcarbamoyl]benzoic acid

The title compound (36 mg) was obtained from intermediate 34 (40 mg,0.15 mmol) and phthalic anhydride (43 mg, 0.29 mmol) as a white solid.M.P.: 148.2-150.5° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.05 (s, 1H),10.22 (s, 1H), 7.84 (d, J 7.7, 1H), 7.69-7.51 (m, 8H), 7.36 (t, J 74,1H), 7.22 (dd, J 1.8, 9.7, 1H).

Example 442-[3-Chloro-3′-(difluoromethoxy)-5-fluorobiphenyl-4-ylcarbamoyl]benzoicacid

The title compound (41 mg) was obtained from intermediate 35 (40 mg,0.14 mmol) and phthalic anhydride (41 mg, 0.28 mmol) as a white solid.M.P.: 156.5-159.5° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.03 (s, 1H),10.26 (s, 1H), 7.83 (d, J 7.6, 1H), 7.79 (s, 1H), 7.75-7.70 (m, 1H),7.69-7.58 (m, 5H), 7.54 (t, J 6.1, 1H), 7.37 (t, J 74, 1H), 7.22 (dd, J1.8, 7.8, 1H).

Example 452-(2′-Chloro-3,5-difluoro-5′-methoxybiphenyl-4-ylcarbamoyl)benzoic acid

The title compound (41 mg) was obtained from intermediate 36 (40 mg,0.15 mmol) and phthalic anhydride (44 mg, 0.3 mmol) as a white solid.M.P.: 167-172° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.06 (s, 1H), 10.23(s, 1H), 7.85 (d, J 7.6, 1H), 7.69-7.65 (m, 1H), 7.62-7.55 (m, 2H), 7.48(d, J 8.6, 1H), 7.29 (d, J 8.3, 2H), 7.08-7.00 (m, 2H), 2.49 (s, 3H).

Example 46 2-(3,3′,5-Trifluoro-5′-methoxybiphenyl-4-ylcarbamoyl)benzoicacid

The title compound (37 mg) was obtained from intermediate 37 (40 mg,0.15 mmol) and phthalic anhydride (46 mg, 0.31 mmol) as a white solid.M.P.: 166.2-167.8° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.04 (s, 1H),10.22 (s, 1H), 7.84 (d, J 7.6, 1H), 7.70-7.52 (m, 5H), 7.23 (d, J 9.8,1H), 7.18 (s, 1H), 6.88 (d, J 10.8, 1H), 3.85 (s, 3H).

Example 472-[4-(Benzo[d][1,3]dioxol-5-yl)-2,6-difluorophenylcarbamoyl]benzoic acid

The title compound (37 mg) was obtained from intermediate 38 (40 mg,0.15 mmol) and phthalic anhydride (46 mg, 0.31 mmol) as a white solid.M.P.: 166.2-167.8° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.02 (s, 1H),10.14 (s, 1H), 7.83 (d, J 5.9, 1H), 7.67-7.64 (m, 1H), 7.60-7.56 (m,2H), 7.47 (d, J 9.2, 2H), 7.38 (s, 1H), 7.26 (dd, J 1.5, 8.2, 1H), 7.01(d, J 8.1, 1H), 6.07 (s, 2H).

Example 482-[4-(Benzo[d][1,3]dioxol-5-yl)-2-chloro-6-fluorophenylcarbamoyl]benzoicacid

The title compound (23 mg) was obtained from intermediate 39 (50 mg,0.19 mmol) and phthalic anhydride (55 mg, 0.38 mmol) as a white solid.M.P.: 182-184.5° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.00 (s, 1H),10.21 (s, 1H), 7.81 (d, J 7.5, 1H), 7.68-7.56 (m, 5H), 7.39 (s, 1H),7.26 (dd, J 1.4, 9.4, 1H), 7.01 (d, J 8.1, 1H), 6.08 (s, 2H).

Example 49 2-(3,5-Difluoro-3′,4′-dimethoxybiphenyl-4-ylcarbamoyl)benzoicacid

The title compound (23 mg) was obtained from intermediate 40 (50 mg,0.19 mmol) and phthalic anhydride (55 mg, 0.38 mmol) as a white solid.M.P.: 182-184.5° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.03 (s, 1H),10.14 (s, 1H), 7.83 (d, J 7.6, 1H), 7.67-7.64 (m, 1H), 7.58 (t, J 7.1,2H), 7.52 (d, J 9.3, 2H), 7.33-7.28 (m, 2H), 7.04 (d, J 9, 1H), 3.86 (s,3H), 3.79 (s, 3H).

Example 50 2-(3,3′,5-Trifluoro-5′-methoxybiphenyl-4-ylcarbamoyl)benzoicacid

The title compound (35 mg) was obtained from intermediate 41 (40 mg,0.14 mmol) and phthalic anhydride (44 mg, 0.28 mmol) as a white solid.M.P.: 164-166° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.02 (s, 1H), 10.25(s, 1H), 7.85-7.78 (m, 2H), 7.73 (d, J 11.2, 1H), 7.69-7.56 (m, 3H),7.24 (d, J 9.9, 1H), 7.18 (s, 1H), 6.88 (d, J 10.8, 1H), 3.85 (s, 3H).

Example 512-(3,3′-Dichloro-5-fluoro-5′-methoxybiphenyl-4-ylcarbamoyl)benzoic acid

The title compound (41 mg) was obtained from intermediate 42 (40 mg,0.14 mmol) and phthalic anhydride (44 mg, 0.28 mmol) as a white solid.M.P.: 159.6-161.2° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.01 (s, 1H),10.25 (s, 1H), 7.82 (d, J 7.9, 1H), 7.79 (s, 1H), 7.74 (d, J 10.7, 1H),7.69-7.57 (m, 3H), 7.43 (s, 1H), 7.28 (s, 1H), 7.08 (s, 1H), 3.86 (s,3H).

Example 522-[4-(2,3-Dihydrobenzofuran-5-yl)-2,6-difluorophenylcarbamoyl]benzoicacid

The title compound (46 mg) was obtained from intermediate 43 (50 mg, 0.2mmol) and phthalic anhydride (59 mg, 0.40 mmol) as a white solid. M.P.:176-177.5° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.02 (s, 1H), 10.12 (s,1H), 7.83 (d, J 7.6, 1H), 7.67 (s, 2H), 7.61-7.53 (m, 2H), 7.49 (d, J7.6, 1H), 7.43 (d, J 9.2, 2H), 6.84 (d, J 8.3, 1H), 4.57 (t, J 8.7, 2H),3.23 (t, J 8.6, 2H).

Example 532-[2-Chloro-4-(2,3-dihydrobenzofuran-5-yl)-6-fluorophenylcarbamoyl]benzoicacid

The title compound (44 mg) was obtained from intermediate 44 (40 mg,0.15 mmol) and phthalic anhydride (44 mg, 0.30 mmol) as a white solid.M.P.: 177-179° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.01 (s, 1H), 10.18(s, 1H), 7.82 (d, J 7.6, 1H), 7.69-7.55 (m, 6H), 7.50 (d, J 8.2, 1H),6.85 (d, J 8.4, 1H), 4.58 (t, J 8.8, 2H), 3.23 (t, J 8.8, 2H).

Example 542-[4-(1,3-Dimethyl-1H-indazol-5-yl)-2,6-difluorophenylcarbamoyl]benzoicacid

The title compound (16 mg) was obtained from intermediate 45 (25 mg,0.09 mmol) and phthalic anhydride (27 mg, 0.18 mmol) as a white solid.M.P.: 276.4-277.5° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.02 (s, 1H),10.14 (s, 1H), 8.14 (s, 1H), 7.83 (d, J 7.2, 1H), 7.79 (d, J 9, 1H),7.68-7.57 (m, 6H), 3.98 (s, 1H), 2.53 (s, 3H).

Example 552-(3′-Chloro-3,5-difluoro-5′-methoxybiphenyl-4-ylcarbamoyl)benzoic acid

The title compound (37 mg) was obtained from intermediate 46 (35 mg,0.13 mmol) and phthalic anhydride (39 mg, 0.25 mmol) as a white solid.M.P.: 171-175° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.04 (s, 1H), 10.22(s, 1H), 7.83 (d, J 7.7, 1H), 7.70-7.55 (m, 5H), 7.42 (s, 1H), 7.28 (s,1H), 7.07 (s, 1H), 3.85 (s, 3H).

Example 562-(3-Chloro-5-fluoro-3′,4′-dimethoxybiphenyl-4-ylcarbamoyl)benzoic acid

The title compound (24 mg) was obtained from intermediate 47 (30 mg, 0.1mmol) and phthalic anhydride (31 mg, 0.2 mmol) as a white solid. M.P.:179.6-182.1° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.0 (s, 1H), 10.18(s, 1H), 7.82 (d, J 7.7, 1H), 7.72 (s, 1H), 7.68-7.57 (m, 4H), 7.33-7.28(m, 2H), 7.04 (d, J 8.8, 1H), 3.86 (s, 3H), 3.79 (s, 3H).

Example 572-(2′,3-Dichloro-5-fluoro-5′-methoxybiphenyl-4-ylcarbamoyl)benzoic acid

The title compound (54 mg) was obtained from intermediate 48 (30 mg, 0.1mmol) and phthalic anhydride (30 mg, 0.2 mmol) as a white solid. M.P.:165-167° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.03 (s, 1H), 10.27 (s,1H), 7.83 (d, J 7.4, 1H), 7.70-7.57 (m, 3H), 7.51-7.47 (m, 2H), 7.43 (d,J 10, 1H), 7.08-7.01 (m, 2H), 3.80 (s, 3H).

Example 58 2-(2′,3,5-Trifluoro-5′-methoxybiphenyl-4-ylcarbamoyl)benzoicacid

The title compound (23 mg) was obtained from intermediate 49 (30 mg, 0.1mmol) and phthalic anhydride (38 mg, 0.22 mmol) as a white solid. M.P.:173.4-176.5° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.04 (s, 1H), 10.24(s, 1H), 7.84 (d, J 7.7, 1H), 7.67 (t, J 7.1, 1H), 7.60 (t, J 8, 2H),7.41 (d, J 8.6, 2H), 7.27 (t, J 9.5, 1H), 7.15-7.12 (m, 1H), 7.03-6.96(m, 1H), 3.80 (s, 3H).

Example 592-(4′-Chloro-3,5-difluoro-3′-methoxybiphenyl-4-ylcarbamoyl)benzoic acid

The title compound (42 mg) was obtained from intermediate 50 (80 mg, 0.3mmol) and phthalic anhydride (85 mg, 0.6 mmol) as a white solid. M.P.:156.1-158.3° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.04 (s, 1H), 10.21(s, 1H), 7.84 (d, J 12.6, 2H), 7.70-7.57 (m, 4H), 7.55-7.49 (m, 1H),7.46 (s, 1H), 7.34 (d, J 8.1, 1H), 3.97 (s, 3H).

Example 602-(3,4′-Dichloro-5-fluoro-3′-methoxybiphenyl-4-ylcarbamoyl)benzoic acid

The title compound (63 mg) was obtained from intermediate 51 (80 mg,0.27 mmol) and phthalic anhydride (83 mg, 0.55 mmol) as a white solid.M.P.: 147.6-150.4° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.02 (s, 1H),10.24 (s, 1H), 7.85-7.79 (m, 2H), 7.73 (d, J 7.8, 1H), 7.70-7.58 (m,3H), 7.51 (d, J 8.1, 1H), 7.46 (s, 1H), 7.34 (d, J 6.5, 1H), 3.97 (s,3H).

Example 612-(3-chloro-2′,5-difluoro-5′-methoxybiphenyl-4-ylcarbamoyl)benzoic acid

The title compound (40 mg) was obtained from intermediate 52 (70 mg,0.26 mmol) and phthalic anhydride (76 mg, 0.52 mmol) as an off-whitesolid. M.P.: 160.1-163.5° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.05 (s,1H), 10.28 (s, 1H), 7.83 (d, J 7.3, 1H), 7.70-7.51 (m, 5H), 7.28 (d, J9.5, 1H), 7.17-7.11 (m, 1H), 7.05-6.97 (m, 1H), 3.81 (s, 3H).

Example 62 2-(3,4′,5-trifluoro-3′-methoxybiphenyl-4-ylcarbamoyl)benzoicacid

The title compound (60 mg) was obtained from intermediate 53 (200 mg,0.79 mmol) and phthalic anhydride (230 mg, 1.58 mmol) as an off-whitesolid. M.P.: 125.6-128.8° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.04 (s,1H), 10.18 (s, 1H), 7.83 (d, J 7.6, 1H), 7.68-7.64 (m, 1H), 7.63-7.54(m, 4H), 7.50 (d, J 8, 1H), 7.35-7.28 (m, 2H), 3.94 (s, 3H).

Example 632-[2,6-difluoro-4-(3-methyl-1H-indol-5-yl)phenylcarbamoyl]benzoic acid

The title compound (84 mg) was obtained from intermediate 54 (66 mg,0.25 mmol) and phthalic anhydride (75 mg, 0.51 mmol) as a white solid.M.P.: 182-186.5° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.03 (s, 1H),10.86 (s, 1H), 10.11 (s, 1H), 7.87 (s, 1H), 7.83 (d, J 7.3, 1H),7.69-7.63 (m, 1H) 7.62-7.57 (m, 2H), 7.52 (d, J 9.3, 2H), 7.45 (d, J8.5, 1H), 7.40 (d, J 8.4, 1H), 7.15 (s, 1H), 2.31 (s, 3H).

Example 642-[2,6-difluoro-4-(3-methyl-1H-indazol-5-yl)phenylcarbamoyl]benzoic acid

The title compound (38 mg) was obtained from intermediate 55 (50 mg,0.19 mmol) and phthalic anhydride (57 mg, 0.39 mmol) as a white solid.M.P.: 179-184° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 12.79 (bs, 1H),10.15 (s, 1H), 8.14 (s, 1H), 7.84 (d, J 7.3, 1H), 7.73 (d, J 7.3, 1H),7.69-7.65 (m, 1H), 7.62-7.55 (m, 4H), 7.53 (d, J 8.7, 1H), 6.02 (bs,1H), 2.54 (s, 3H).

Example 65 2-(3-chloro-3′-ethyl-5-fluorobiphenyl-4-ylcarbamoyl)benzoicacid

The title compound (38 mg) was obtained from intermediate 56 (50 mg,0.19 mmol) and phthalic anhydride (57 mg, 0.39 mmol) as a white solid.M.P.: 179-184° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.02 (bs, 1H),10.22 (s, 1H), 7.82 (d, J 7.7, 1H), 7.74-7.54 (m, 7H), 7.39 (t, J 7.6,1H), 7.27 (d, J 7.6, 1H). 2.68 (q, J 7.6, 2H), 1.23 (t, J 7.6, 3H).

Example 662-(3-chloro-3′-ethoxy-2′,5-difluorobiphenyl-4-ylcarbamoyl)benzoic acid

The title compound (54 mg) was obtained from intermediate 57 (60 mg,0.21 mmol) and phthalic anhydride (63 mg, 0.42 mmol) as a white solid.M.P.: 160-163° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.04 (s, 1H), 10.29(s, 1H), 7.83 (d, J 7.6, 1H), 7.70-7.55 (m, 4H), 7.51 (d, J 10, 1H),7.26-7.21 (m, 2H), 7.16-7.10 (m, 1H), 4.14 (q, J 6.8, 2H), 1.37 (t, J6.8, 3H).

Example 672-[2-chloro-4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-fluorophenylcarbamoyl]benzoicacid

The title compound (54 mg) was obtained from intermediate 58 (60 mg,0.21 mmol) and phthalic anhydride (63 mg, 0.42 mmol) as a white solid.M.P.: 147-151° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.02 (s, 1H), 10.19(s, 1H), 7.82 (d, J 7.5, 1H), 7.68-7.53 (m, 5H), 7.29 (d, J 2.1, 1H),7.24 (dd, J 2.1, 8.4, 1H), 6.94 (d, J 8.4, 1H), 4.28 (s, 4H).

Example 682-[3-chloro-5-fluoro-3′-(2,2,2-trifluoroethoxy)biphenyl-4-ylcarbamoyl]benzoicacid

The title compound (21 mg) was obtained from intermediate 59 (80 mg,0.25 mmol) and phthalic anhydride (74 mg, 0.5 mmol) as a white solid.M.P.: 133-137° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.02 (s, 1H), 10.25(s, 1H), 7.86-7.79 (m, 2H), 7.72 (d, J 10.5, 1H), 7.70-7.55 (m, 3H),7.48-7.42 (m, 3H), 7.15-7.06 (m, 1H), 4.88 (q, J 9.3, 2H).

Example 69 2-(3-fluoro-3′-methoxybiphenyl-4-ylcarbamoyl)benzoic acid

The title compound (82 mg) was obtained from intermediate 60 (150 mg,0.69 mmol) and phthalic anhydride (200 mg, 1.4 mmol) as a white solid.M.P.: 141-143° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.04 (s, 1H), 10.23(s, 1H), 7.97-7.93 (m, 1H), 7.87 (d, J 7.5, 1H), 7.70-7.50 (m, 5H), 7.37(t, J 7.9, 1H), 7.29-7.20 (m, 2H), 6.94 (d, J 6.1, 1H), 3.82 (s, 3H).

Example 70 2-(3′-ethoxybiphenyl-4-ylcarbamoyl)benzoic acid

The title compound (82 mg) was obtained from intermediate 61 (150 mg,0.69 mmol) and phthalic anhydride (200 mg, 1.4 mmol) as a white solid.M.P.: 141-143° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.03 (s, 1H), 10.41(s, 1H), 7.87 (d, J 7.6, 1H), 7.76 (d, J 8.6, 2H), 7.69-7.61 (m, 3H),7.60-7.52 (m, 2H), 7.33 (t, J 7.9, 1H), 7.20 (d, J 7.8, 1H), 7.14 (s,1H), 6.87 (dd, J 2.1, 8.0, 1H), 4.07 (q, J 7, 2H), 1.34 (t, J 7, 2H).

Example 71 2-[3′-(ethylthio)-3,5-difluorobiphenyl-4-ylcarbamoyl]benzoicacid

The title compound (65 mg) was obtained from intermediate 62 (150 mg,0.69 mmol) and phthalic anhydride (200 mg, 1.4 mmol) as a white solid.M.P.: 137.8-142.1° C. ¹H-NMR (8 ppm, DMSO-d₆, 400 MHz): 13.03 (s, 1H),10.2 (s, 1H), 7.84 (d, J 7.6, 1H), 7.70-7.52 (m, 7H), 7.42 (t, J 7.7,1H), 7.34 (d, J 7.6, 1H), 3.08 (q, J 7.3, 2H), 1.26 (t, J 7.3, 3H). MS(m/z): 413.80 ([M+H]⁺).

Example 722-[3′-(ethylsulfinyl)-3,5-difluorobiphenyl-4-ylcarbamoyl]benzoic acid

Oxone (241 mg, 0.39 mmol) was added to a solution of example 71 (210 mg,0.43 mmol) in water-acetone (1:1, 4.2 ml) and stirred at RT for 2 h.Solid that formed in reaction mixture was filtered and dried to obtainthe title compound (95 mg) as a white solid. ¹H-NMR (δ ppm, DMSO-d₆, 400MHz): 13.04 (s, 1H), 10.26 (s, 1H), 8.19 (s, 1H), 8.14 (d, J 7.8, 1H),7.91 (d, J 7.8, 1H), 7.84 (d, J 7.3, 1H), 7.77 (t, J 7.8, 1H), 7.72-7.64(m, 3H), 7.62-7.56 (m, 2H), 3.41 (q, J 7.3, 2H), 1.13 (t, J 7.3, 3H). MS(m/z): 430.07 ([M+H]⁺).

Example 73 2-(3′-cyclopropoxy-3,5-difluorobiphenyl-4-ylcarbamoyl)benzoicacid

The title compound (96 mg) was obtained from intermediate 63 (160 mg,0.61 mmol) and phthalic anhydride (181 mg, 1.2 mmol) as a white solid.M.P.: 125-127° C. MS (m/z): 410.2 ([M+H]⁺).

Example 742-(3′-ethoxy-3,5-difluorobiphenyl-4-ylcarbamoyl)-6(5)-methylbenzoic acid

The title compound (75 mg) was obtained from intermediate 5 (200 mg, 0.8mmol) and 4-methylisobenzofuran-1,3-dione (260 mg, 1.6 mmol) as a whitesolid. M.P.: 138-140° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.02 (s,1H), 10.09 (s, 1H), 7.77 (d, J 7.8, 1H), 7.52 (d, J 9.3, 3H), 7.47-7.41(m, 1H), 7.38 (t, J 7.9, 1H), 7.32-7.24 (m, 2H), 6.98-6.95 (m, 1H), 4.11(q, J 6.9, 2H), 2.41 (s, 3H), 1.35 (t, J 6.9, 3H). MS (m/z): 410.07([M−H]⁻).

Example 752-[4-(3-ethyl-1H-indol-5-yl)-2,6-difluorophenylcarbamoyl]benzoic acid

The title compound (75 mg) was obtained from intermediate 65 (250 mg,0.992 mmol) and phthalic anhydride (271 mg, 1.84 mmol) as a white solid.M.P.: 157.9-160.9° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.03 (s, 1H),10.88 (s, 1H), 10.11 (s, 1H), 7.89 (s, 1H), 7.83 (d, J 7.3, 1H),7.69-7.63 (m, 1H), 7.62-7.56 (m, 2H), 7.51 (d, J 9.3, 2H), 7.47-7.39 (m,2H), 7.16 (s, 1H), 2.75 (q, J 7.4, 2H), 1.28 (t, J 7.4, 3H). MS (m/z):418.75 ([M−H]⁻).

Example 76 2-(3′-ethoxy-3,5-difluorobiphenyl-4-ylcarbamoyl)nicotinicacid

The title compound (15 mg) was obtained from intermediate 5 (150 mg, 0.6mmol) and furo[3,4-b]pyridine-5,7-dione (180 mg, 1.2 mmol) as a greysolid. M.P.: 207-210° C. MS (m/z): 399.08 ([M+H]⁺).

Example 77 4-(3′-ethoxy-3,5-difluorobiphenyl-4-ylcarbamoyl)nicotinicacid

The title compound (10 mg) was obtained from intermediate 5 (100 mg, 0.4mmol) and furo[3,4-c]pyridine-1,3-dione (119 mg, 0.8 mmol) as a whitesolid. M.P.: 219-221° C. MS (m/z): 399.01 ([M+H]⁺). The regiochemicalassignment is based on earlier reports, e.g. Nailton et. al. Bioorganic& Medicinal Chemistry Letters 2010, 20(1), 74-77.

Example 782-[3′-(ethylthio)-2,3,5,6-tetrafluorobiphenyl-4-ylcarbamoyl]benzoic acid

The title compound (82 mg) was obtained from intermediate 66 (280 mg,0.93 mmol) and phthalic anhydride (206 mg, 1.4 mmol) as a white solid.M.P.: 158-160° C. MS (m/z): 448.29 ([M−H]⁻).

Example 792-(2′-chloro-2-fluoro-5′-methoxybiphenyl-4-ylcarbamoyl)benzoic acid

The title compound (50 mg) was obtained from intermediate 67 (210 mg,0.83 mmol) and phthalic anhydride (185 mg, 1.2 mmol) as a grey solid.M.P.: 185-187° C. MS (m/z): 398.24 ([M−H]⁻).

Example 80 2-(3-fluoro-3′-propoxybiphenyl-4-ylcarbamoyl)benzoic acid

The title compound (14 mg) was obtained from intermediate 68 (170 mg,0.7 mmol) and phthalic anhydride (153 mg, 1.03 mmol) as a white solid.M.P.: 116-119° C. MS (m/z): 394.2 ([M+H]⁺).

Example 81 2-(3′-propoxybiphenyl-4-ylcarbamoyl)benzoic acid

The title compound (60 mg) was obtained from intermediate 69 (60 mg,0.26 mmol) and phthalic anhydride (58 mg, 0.4 mmol) as a white solid.M.P.: 152-154° C. MS (m/z): 376.2 ([M+H]⁺).

Example 82 2-[3′-(ethylthio)-2-fluorobiphenyl-4-ylcarbamoyl]benzoic acid

The title compound (200 mg) was obtained from intermediate 70 (430 mg,1.74 mmol) and phthalic anhydride (380 mg, 2.6 mmol) as a white solid.M.P.: 74-76° C. MS (m/z): 395.72 ([M+H]⁺).

Example 832-[3,5-difluoro-3′-(2,2,2-trifluoroethoxy)biphenyl-4-ylcarbamoyl]benzoicacid

The title compound (80 mg) was obtained from intermediate 71 (88 mg,0.29 mmol) and phthalic anhydride (86 mg, 0.58 mmol) as a white solid.M.P.: 152-156° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.04 (s, 1H), 10.19(s, 1H), 7.84 (d, J 7.2, 1H), 7.68-7.53 (m, 6H), 7.46-7.41 (m, 2H),7.13-7.06 (m, 1H), 4.87 (q, J 9, 2H).

Example 84 2-(3′-ethyl-3,5-difluorobiphenyl-4-ylcarbamoyl)benzoic acid

The title compound (15 mg) was obtained from intermediate 72 (170 mg,0.73 mmol) and phthalic anhydride (210 mg, 1.45 mmol) as a white solid.M.P.: 132-136° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.04 (s, 1H), 10.18(s, 1H), 7.83 (d, J 7.3, 1H), 7.69-7.48 (m, 7H), 7.39 (t, J 7.6, 1H),7.26 (d, J 7.3, 1H), 2.67 (q, J 7.6, 2H), 1.23 (t, J 7.6, 3H).

Example 85 2-(biphenyl-4-ylcarbamoyl)benzoic acid

The title compound (46 mg) was obtained from biphenyl-4-amine (65 mg,0.38 mmol) and phthalic anhydride (85 mg, 0.58 mmol) as a white solid.M.P.: 276-278° C. MS (m/z): 318.1 ([M+H]⁺).

Example 86 2-(2′-chlorobiphenyl-4-ylcarbamoyl)benzoic acid

The title compound (223 mg) was obtained from intermediate 73 (170 mg,0.83 mmol) and phthalic anhydride (185 mg, 1.25 mmol) as a white solid.M.P.: 243-247° C. MS (m/z): 352.1 ([M+H]⁺).

Example 87 2-(3′-methoxybiphenyl-4-ylcarbamoyl)benzoic acid

The title compound (223 mg) was obtained from intermediate 74 (170 mg,0.83 mmol) and phthalic anhydride (185 mg, 1.25 mmol) as a white solid.M.P.: 243-247° C. MS (m/z): 348.2 ([M+H]⁺).

Example 88 2-[3′-(trifluoromethoxy)biphenyl-4-ylcarbamoyl]benzoic acid

The title compound (110 mg) was obtained from intermediate 75 (280 mg,1.1 mmol) and phthalic anhydride (245 mg, 1.66 mmol) as a white solid.M.P.: 154.4-158.5° C. MS (m/z): 402.2 ([M+H]⁺).

Example 89 2-[3′-(ethylthio)-2,6-difluorobiphenyl-4-ylcarbamoyl]benzoicacid

The title compound (50 mg) was obtained from intermediate 76 (240 mg,0.9 mmol) and phthalic anhydride (200 mg, 1.35 mmol) as a white solid.M.P.: 162-167° C. MS (m/z): 414.2 ([M+H]⁺).

Example 90 2-(3′-ethylbiphenyl-4-ylcarbamoyl)benzoic acid

The title compound (96 mg) was obtained from intermediate 77 (100 mg,0.5 mmol) and phthalic anhydride (110 mg, 0.76 mmol) as an off-whitesolid. M.P.: 178-182° C. MS (m/z): 346.2 ([M+H]⁺).

Example 912-(3′-butoxy-2,3,5,6-tetrafluorobiphenyl-4-ylcarbamoyl)benzoic acid

The title compound (130 mg) was obtained from intermediate 78 (180 mg,0.57 mmol) and phthalic anhydride (127 mg, 0.86 mmol) as a white solid.M.P.: 215.5-218.5° C. MS (m/z): 460.18 ([M−H]⁻).

Example 92 2-(3′-butoxy-3-fluorobiphenyl-4-ylcarbamoyl)benzoic acid

The title compound (130 mg) was obtained from intermediate 79 (170 mg,0.65 mmol) and phthalic anhydride (145 mg, 0.98 mmol) as a white solid.M.P.: 102-105° C. MS (m/z): 406.17 ([M−H]⁻).

Example 932-[3,5-difluoro-3′-(trifluoromethoxy)biphenyl-4-ylcarbamoyl]benzoic acid

The title compound (50 mg) was obtained from intermediate 8 (200 mg,0.69 mmol) and phthalic anhydride (150 mg, 1.03 mmol) as a white solid.M.P.: 158-160° C. MS (m/z): 435.93 ([M−H]⁻).

Example 94 2-(3′-cyclopropoxy-3-fluorobiphenyl-4-ylcarbamoyl)benzoicacid

The title compound (120 mg) was obtained from intermediate 80 (100 mg,0.41 mmol) and phthalic anhydride (91 mg, 0.62 mmol) as a white solid.M.P.: 134.5-137.5° C. MS (m/z): 390.27 ([M−H]⁻).

Example 95 2-(3′-cyclopropoxybiphenyl-4-ylcarbamoyl)benzoic acid

The title compound (90 mg) was obtained from intermediate 81 (98 mg,0.43 mmol) and phthalic anhydride (96 mg, 0.65 mmol) as a white solid.M.P.: 150.2-154.3° C. MS (m/z): 372.14 ([M−H]⁻).

Example 96 2-(3′-butoxybiphenyl-4-ylcarbamoyl)benzoic acid

The title compound (37 mg) was obtained from intermediate 82 (80 mg,0.33 mmol) and phthalic anhydride (73 mg, 0.5 mmol) as a white solid.M.P.: 155-157° C. MS (m/z): 388.38 ([M−H]⁻).

Example 97 2-(3′-butoxy-2-fluorobiphenyl-4-ylcarbamoyl)benzoic acid

The title compound (171 mg) was obtained from intermediate 83 (240 mg,0.92 mmol) and phthalic anhydride (205 mg, 1.3 mmol) as a white solid.M.P.: 164-167° C. MS (m/z): 406.31 ([M−H]⁻).

Example 98 2-(3′-Butoxy-2,6-difluorobiphenyl-4-ylcarbamoyl)benzoic acid

The title compound (91 mg) was obtained from intermediate 84 (170 mg,0.6 mmol) and phthalic anhydride (136 mg, 0.9 mmol) as an off-whitesolid. M.P.: 181.1-184.2° C. MS (m/z): 423.95 ([M−H]⁻).

Example 992-[2,6-Difluoro-4-(3-propyl-1H-indol-5-yl)phenylcarbamoyl]benzoic acid

The title compound (150 mg) was obtained from intermediate 86 (240 mg,0.84 mmol) and phthalic anhydride (186 mg, 1.25 mmol) as a white solid.M.P.: 76-80° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 10.88 (s, 1H), 7.88(s, 1H), 7.81 (d, J 6.6, 1H), 7.75-7.71 (m, 1H), 7.53-7.47 (m, 5H),7.44-7.38 (m, 2H), 7.14 (s, 1H), 2.72 (t, J 7.4, 2H), 1.69 (h, J 7.5,2H), 0.96 (t, J 7.3, 3H). MS (m/z): 433.13 ([M−H]⁻).

Example 1002-[2-Chloro-4-(3-ethyl-1H-indol-5-yl)-6-fluorophenylcarbamoyl]benzoicacid

The title compound (25 mg) was obtained from intermediate 87 (60 mg,0.21 mmol) and phthalic anhydride (46 mg, 0.31 mmol) as a white solid.M.P.: 98-102° C. MS (m/z): 435.23 ([M−H]⁻).

Biological Assay

The properties of the compounds of this invention may be confirmed by anumber of biological and pharmacological assays. The biological andpharmacological assay which can be been carried out with the compoundsaccording to the invention and/or their pharmaceutically acceptablesalts are exemplified below. Similarly the compounds of the presentinvention may also be tested using other assays such as cytokine (IL-17and interferon gamma) estimation in human whole blood and PBMCs.

The compounds of the invention may also be tested in various animalmodels to establish the various therapeutic potential of the compoundsof this invention.

1. In-Vitro DHODH Inhibition Assays

The properties of the compounds of this invention may be confirmed by anumber of biological/pharmacological assays. Thebiological/pharmacological assay which can be been carried out with thecompounds according to the invention and/or their pharmaceuticallyacceptable salts is exemplified below. Similarly the compounds of thepresent invention may also be tested using other assays such as cytokine(IL-17, interferon gamma etc.) estimation in human whole blood andPBMCs.

Dihydro-Orotate Dehydrogenase Inhibition Assay

Dihydro-orotate dehydrogenase (DHODH) catalyzes the reduction ofdihydro-orotate to orotate during de novo biosynthesis of pyrimidines.Inhibition of DHODH activity in U937 membrane preparations was measuredby the dihydro-orotate driven reduction of 2,6 dichloroindophenol(DCIP).

U937 cells were homogenized in 20 mM Tris/HCl (pH 7.2) containing 1 mMEDTA. Cell debris was removed by centrifugation at 2000×g for 10 min.Membrane fractions were pelleted by centrifuging the supernatant at160000×g for 1 h at 4° C. and washed with buffer containing 125 mMsucrose and 150 mM NaCl. Following washes, the pellet was dissolved in20 mM Tris/HCl containing 150 mM NaCl, 1 mM EDTA, and 1% octyl glucosideon ice for 1 h. Particulate matter was removed by centrifugation at100000×g for 1 h at 4° C. Extracts (˜50 μg protein) were added to anassay mixture (200 μM CoQD, 500 μM dihydro-orotate, 75 μM DCIP in 100 mMHEPES pH 8.0, 150 mM NaCl, 10% glycerol, 0.05% Triton X-100) containinginhibitors at desired concentrations in a 96-well plate. The mixture wasincubated at 37° C. for 4 h before measuring the change in absorbance ona plate reader (BMG Labtech., Germany) at 600 nm. Data were analyzedusing GraphPad Prism. IC₅₀ for each compound was determined based on thepercent inhibition of dihydro-orotate reduction.

Results:

TABLE 2 h- DHODH % inhibition Compound 1 uM IC50 (nM) Teriflunomide^(#)77.16 875.9 Example 1 53.27 740.8 Example 2 12.18 Example 3 14.27Example 4 42.95 Example 5 85.70 49.8 Example 6 2.26 Example 7 4.53Example 8 85.75 90.03 Example 9 10.33 Example 10 46.78 Example 11 —Example 12 64.47 204.7 Example 13 76.36 150 Example 14 52.19 Example 1575.48 129.2 Example 16 28.04 Example 17 50.26 Example 18 62.23 294.1Example 19 82.18 44.65 Example 20 55.37 Example 21 56.44 Example 2241.83 Example 23 47.16 Example 24 40.18 Example 25 60.17 Example 2685.34 122 Example 27 82.93 147.5 Example 28 12.90 Example 29 94.02 7.93Example 30 67.97 Example 31 73.51 44.65 Example 32 58.91 Example 33Example 34 95.78 62.52 Example 35 86.45 11.85 Example 36 — Example 3714.77 Example 38 27.84 Example 39 74.43 177.8 Example 40 — Example 4172.16 83.39 Example 42 76.91 24.04 Example 43 58.24 180.8 Example 4471.12 90.63 Example 45 96.21 44.09 Example 46 55.97 Example 47 55.19Example 48 47.10 Example 49 — Example 50 28.65 Example 51 26.56 Example52 12.82 Example 53 — Example 54 — Example 55 44.50 Example 56 1.77Example 57 68.11 Example 58 76.14 Example 59 34.54 Example 60 41.77Example 61 73.73 Example 62 12.37 Example 63 76.68 22.0 Example 64 23.37Example 65 71.16 146.2 Example 66 87.51 84.42 Example 67 54.12 Example68 86.47 62.2 Example 69 21.98 Example 70 14.02 Example 71 84.84 53.51Example 72 16.92 Example 73* 84.98 28.01 Example 74* 7.14 Example 75*100 1.52 Example 76* 44.05 Example 77* 50.22 Example 78* 32.92 Example79* — Example 80* 47.65 Example 81* 11.25 Example 82* 57.87 Example 83*43.56 Example 84* 36.61 Example 85* 15.13 Example 86* 33.61 Example 87*30.25 Example 88* 62.18 Example 89 — Example 90 29.41 Example 91 42.39Example 92 9.65 Example 93 10.46 Example 94 13.86 Example 95 1.49Example 96 — Example 97 — Example 98 30.97 Example 99 42.58 Example 10058.71 ^(#)compound tested at 10 uM; *compound tested at 0.3 uM2. Inhibition of IL-17 Release from Mouse Splenocytes:

Splenocytes isolated from Balb/c mice were re-suspended in RPMI mediumat a concentration of 1×10⁶ cells/ml and seeded in a 6 well plate. Cellswere incubated with desired concentrations of the inhibitor for 15 minprior to induction with 10 ng/ml PMA+1 μM ionomycin. After a 3 hincubation, supernatant was collected and analyzed for IL-17concentration using an ELISA kit. Data were analysed using GraphPadPrism. IC₅₀ values for each compound were determined based on thepercent inhibition due to the test compound compared to the control.

Results:

TABLE 3 IL-17 _% inhibition @ IC50 Compound 10 μM (μM) Teriflunomide 0Example 1 6.13 Example 2 29.25 Example 3 17.15 Example 4 11.23 Example 530.79 Example 6 9.52 Example 7 8.58 Example 8 35.43 Example 9 26.89Example 10 6.82 Example 11 2.62 Example 12 2.96 Example 13 3.43 Example14 13.49 Example 15 57.45 Example 16 12.35 Example 17 11.11 Example 1812.09 Example 19 19.00 Example 20 24.27 Example 21 17.84 Example 2212.91 Example 23 14.97 Example 24 8.46 Example 25 17.54 Example 26 8.70Example 27 12.39 Example 28 18.83 Example 29 46.09 18.76 Example 3010.29 Example 31 21.10 Example 32 11.83 Example 33 14.02 Example 34 5.96Example 35 7.76 Example 36 45.45 Example 37 17.84 Example 38 9.35Example 39 5.87 Example 40 8.79 Example 41 7.16 Example 42 22.26 Example43 6.82 Example 44 35.00 Example 45 48.51 Example 46 3.69 Example 476.22 Example 48 22.04 Example 49 3.95 Example 50 10.08 Example 51 10.85Example 52 13.77 Example 53 8.28 Example 54 22.56 Example 55 5.66Example 56 5.49 Example 58 5.46 Example 59 7.36 Example 60 20.29 Example61 4.23 Example 62 8.34 Example 63 0 Example 64 15.33 Example 65 11.04Example 67 3.56 Example 69 5.54 Example 70 48.43 9.11 Example 71 27.77Example 72 7.36 Example 73 7.86 Example 74 13.81 Example 75 29.40 32.86Example 76 7.88 Example 77 9.25 Example 78 11.14 Example 79 24.63Example 80 20.07 Example 81 23.00 Example 82 17.59 Example 83 8.79Example 84 12.12 Example 85 13.03 Example 86 23.84 Example 87 20.91Example 88 19.09 Example 89 25.54 Example 90 22.353. Determination of IL-17 Producing Cells by Flow Cytometry:

PBMC isolated from human blood were stimulated and treated with desiredconcentrations of the test compounds prior to stimulation with Cytostim(Milteny Biotech, Germany). After 4 h, IL-17 secreting cells werestained using the IL-17 secretion assay kit as per the manufacturer'sinstruction and normalized to total CD4+ cells within the PBMCpopulation. Data were analyzed using Graph pad prism. For instanceexample 29 showed a 43.6% inhibition of IL17 when tested at at 1 uM. Theresults indicate the potential of the compounds of invention to inhibitIL17 release independent of DHODH inhibition.

4. In Vitro Inhibition of Proliferation and Cytokine Release inPeripheral Blood Mononuclear Cells (PBMC)

a. Inhibition of PHA Induced PBMC Proliferation:

PBMC from freshly collected HWB was isolated by density gradient usingHistopaque and seeded in a 96-well plate. Wells were incubated withdesired concentrations of the inhibitor for 15 min. Proliferation wasinduced by the addition of 2 μM Phytohemagglutinin at 37° C. in anatmosphere containing 95% CO₂. Viability was determined after 48 h usingan 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)assay. Data were analysed using GraphPad Prism. percent inhibitionand/or GI₅₀ values for each compound were determined based on thepercent inhibition due to the test compound compared to the control. Forinstance example 29, 42 & 75 showed a greater than 70% inhibition whentested at 10 uM.

b. Inhibition of PHA Induced Cytokine (IL17) Release:

PBMC from freshly collected HWB were isolated by density gradient usingHistopaque and seeded in a 96-well plate. Wells were incubated withdesired concentrations of the inhibitor for 15 min. Proliferation wasinduced by the addition of 2 μM Phytohemagglutinin at 37° C. in anatmosphere containing 95% CO₂. Supernatant was collected after 48 h forestimation of cytokines by ELISA. Data were analysed using GraphPadPrism. Percent inhibition and IC₅₀ values for each compound weredetermined based on the percent inhibition due to the test compoundcompared to the control. For instance example 5 showed a greater than50% inhibition when tested at 10 uM.

c. Inhibition of PHA Induced CD4+ Cell Proliferation in Human WholeBlood:

HWB or were treated with desired concentration of inhibitor and inducedwith 5 μM PHA. % CD4+ cell viability was determined after 48 h by flowcytometry. Data were analysed using GraphPad Prism. Percent inhibitionand IC₅₀ values for each compound were determined based on the percentinhibition due to the test compound compared to the control. Forinstance example 29 and 75 showed a greater than 65% inhibition whentested at 1 uM.

d. Inhibition of PHA Induced CD4+ Cell Proliferation in PBMC:

Isolated PBMC were treated with desired concentration of inhibitor andinduced with 5 μM PHA. % CD4+ cell viability was determined after 48 hby flow cytometry. Data were analysed using GraphPad Prism. IC₅₀ valuesfor each compound were determined based on the percent inhibition due tothe test compound compared to the control. For instance example 29 and75 showed a greater than 90% inhibition when tested at 1 uM.

5. Single Dose Oral Hepatotoxicity Assay:

BALB/cJ (n=4 or 5/sex) mice aged 8 to 10 weeks, with weights rangingfrom 18 to 25 g were used. They were housed under conditions ofcontrolled temperature and humidity and a 12-h light/dark cycle. Theywere given continuous access to bottled spring water and fed a standardchow at ad libitum. The mice were allowed to acclimate for 1 week beforeuse. On the day of experiment mice were fasted overnight for 12 h andadministered with test item formulation (100 mg/kg·b·wt/po) or vehicle(10 ml/kg·b·wt/po) by oral route and food was given 4 hr after test itemadministration. After 24 hr post administration blood samples werecollected from orbital sinus of all the animals and serum was separatedto assess the hepatotoxicity. Biochemical evaluation of liver functionwas determined by measuring serum enzyme activities of alanineaminotransferase (ALT) and aspartate aminotransferase (AST) usingcommercially available kits from Sigma (St. Louis, Mo.).

Results:

The compounds of the invention were found to be Non-Hepatotoxic and thedata is as disclosed herein below in Table-4.

Total number of AST ALT Group animals (n) (U/L) (U/L) Hepatotoxic ShamControl — 116.2 77.6 NO Vehicle Control 8 131.1 60 NO Vehicle Control 8239.8 96.8 NO Example 5 8 137.8 113.6 NO Example 19 8 126.5 87.9 NOExample 29 8 114.4 67.9 NO Example 31 10 161.4 65.1 NO Example 35 8 172108.3 NO Example 42 10 189.6 113 NO Example 70 8 210.4 84 NO Example 758 210.8 93.9 NO6. Evaluation of Usefulness of DHODH Modulators in VariousAnti-Inflammatory and Autoimmune Disorders Using In-Vivo Animal Modelshas been or can be Established Using the Methodology as Given Below.i. Inhibition of Concanavalin Induced Lymphocyte Proliferation in WistarRats:

Con A is often used to prepare experimental animals with high levels ofcytotoxic T-lymphocytes, because these cells are involved in thedevelopment of viral infections in humans. To evaluate the effect of aninhibitor on lymphocyte proliferation in rats, animals were treated with10 mg/kg po of a compound of the present invention prior to intravenousadministration of 5 mg/kg concanavalin A. Lymphocyte count wasdetermined after 48 h on a Medonic blood analyzer. Data indicated a ˜75%reduction in peripheral blood lymphocytes upon treatment with the testcompound implicating the therapeutic potential of the compound inimmune-mediated disorders such as rheumatoid arthritis.

ii. Inhibition of Concanavalin Induced IL-17 Release in Balb/c Mice:

Balb/c mice were treated with 10 mg/kg po of the test compound prior tointravenous administration of 20 mg/kg concanavalin A. Plasma wasobtained after 2 h and estimated for inhibition of IL-17 release byELISA. The test compound reduced IL-17 secretion from Th17 cells in adose-dependent manner.

iii. Inhibition of TNBS Induced Colitis in Balb/c Mice:

Female BALB/c Mice are to be fasted overnight and administered PBS, 50%Ethanol/PBS, or 50% Ethanol/20 mg/kg TNBS (40 μL enema), while underisoflourane anesthesia (study day 1). Animals are to be dosed p.o. withVehicle, Dexamethasone (5 mg/kg), or test compounds at for example 25mg/kg. The dosing would begin on study day 1 (5 hours after the TNBSenema). Mice are to be euthanized on day 7. Various parameters ofcolitis are to be measured, essentially according to a previouslypublished study (see. Fitzpatrick et al., Inflammatory Bowel Diseases,2010).

Other in-vivo models wherein the effect of DHODH modulators in variousAnti-inflammatory and Autoimmune disorders can be tested includeCollagen-induced arthritis in male DBA/a Ola HSD mice and ChronicExperimental Autoimmune Encephalomyelitis in C57/Bl6J mice: Collageninduced arthritis in rodent models have been widely used to illustrateand understand the development of the disease besides serving as asurrogate for validation of therapeutic targets for human rheumatoidarthritis. Mice are anesthetized with Isoflurane and given 150 μl ofBovine Type II collagen in Freund's complete adjuvant injections (day 0and day 21). Treatment is initiated on study day 0 and continued oncedaily, every day (po, qd). Starting on day 18, clinical scores are givendaily for each of the paws (right front, left front, right rear, leftrear) and continued till the day of sacrifice (day 34).

Experimental Autoimmune Encephalomyelitis (EAE) is an inflammatorydisease of the central nervous system and widely used as an animal modelof Multiple Sclerosis. Animals are administered pertussis toxinintravenously and myelin oligodendrocyte glycoprotein (MOG)subcutaneously on day 0. Treatment is initiated at day 0 and continuedtill sacrifice. Development of EAE is observed between day 9 to day 42.At the end of the treatment period, animals are sacrificed forhistopathological analysis as well as cytokine estimation in plasma.

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and applications of thepresent invention. It is therefore to be understood that numerousmodifications may be made to the illustrative embodiments and that otherarrangements may be devised without departing from the spirit and scopeof the present invention as described above and the appended claim.

All publications and patent and/or patent applications cited in thisapplication are herein incorporated by reference to the same extent asif each individual publication or patent application was specificallyand individually indicated to be incorporated herein by reference.

The invention claimed is:
 1. A compound of formula (I)

or a tautomer, stereoisomer, pharmaceutically acceptable salt,pharmaceutically acceptable ester, or N-oxide thereof, wherein Ring Aincluding substituent R¹ is

Ring B, including X¹, X² and X³ is selected from

wherein Ring A and Ring B may each independently be optionallysubstituted by one or more R⁴ and C* is attached to —NR—; R is hydrogen;L¹ and L² are absent; Cy is selected from the group consisting of

each occurrence of R⁴ is independently selected from the groupconsisting of hydrogen, hydroxy, halogen, cyano, —OR^(a),—S(═O)_(q)—R^(a), —NR^(a)R^(b), —C(═Y)—R^(a), —C(═Y)—OR^(a),—C(═Y)—NR^(a)R^(b), —S(═O)_(q)—NR^(a)R^(b), substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkylakyl, and substituted orunsubstituted cycloalkenyl; each occurrence of R^(a) and R^(b) may bethe same or different and are independently selected from the groupconsisting of hydrogen, halogen, hydroxy, cyano, substituted orunsubstituted (C₁₋₆)alkyl, and —OR^(c) (wherein R^(c) is substituted orunsubstituted (C₁₋₆)alkyl); each occurrence of Y is independentlyselected from the group consisting of O, S and NR^(a); and eachoccurrence of q independently represents 0, 1 or 2 wherein the termsubstituted refers to substitution with any one or any combination ofthe following substituents which may be the same or different and areselected from hydroxy, halogen, carboxyl, cyano, nitro, oxo (═O), thio(═S), unsubstituted alkyl, unsubstituted alkoxy, halo-substitutedalkoxy, unsubstituted alkenyl, unsubstituted (alkynyl, unsubstitutedcycloalkyl, unsubstituted cycloalkenyl, unsubstituted cycloalkylalkyl,unsubstituted cycloalkenylalkyl, unsubstituted heterocyclic ring,unsubstituted heterocycicylalkyl, unsubstituted aryl, unsubstitutedarylalkyl, unsubstituted heteroaryl, unsubstituted heteroarylalkyl,unsubstituted guanidine, —COOR^(x), —C(O)R^(x), —C(S)R^(x),—C(O)NR^(x)R^(y), —C(O)ONR^(x)R^(y), —NR^(y)R^(z), —NR^(x)COR^(y)R^(z),—N(R^(x))SORy, —N(R^(x))SO₂R^(y), —(═N—N(R^(x))R^(y)),—NR^(x)C(O)OR^(y), —NR^(x)C(O)R^(y)—, —NR^(x)C(S)R^(y),—NR^(x)C(S)NR^(y)R^(z), —SONR^(x)R^(y), —SO₂NR^(x)R^(y)—, —OR^(x),—OR^(x)C(O)NR^(y)R^(z), —OR^(x)C(O)OR^(y), —OC(O)R^(x),—OC(0)NR^(x)R^(y), —RxNR^(y)C(O)R^(z), —R^(x)OR^(y), —R^(x)C(O)OR^(y),—R^(x)C(O)NR^(y)R^(z), —R^(x)C(O)R^(x), —R^(x)OC(O)R^(y), —SR^(x),—SOR^(x), —SO₂R^(x), —ONO₂, wherein R^(x), R^(y) and R^(z) in each ofthe above groups can be hydrogen, unsubstituted alkyl, unsubstitutedalkoxy, unsubstituted alkenyl, unsubstituted alkynyl, unsubstitutedcycloalkyl, unsubstituted cycloalkenyl, unsubstituted cycloalkylalkyl,unsubstituted cycloalkenylalkyl, unsubstituted heterocyclic ring,heterocycicylalkyl, unsubstituted aryl, unsubstituted arylalkyl,unsubstituted heteroaryl, unsubstituted heteroarylalkyl.
 2. Apharmaceutical composition, comprising a compound of claim 1 and apharmaceutically acceptable carrier.
 3. The pharmaceutical compositionof claim 2, further comprising one or more additional therapeutic agentsselected from the group consisting of anti-inflammatory agents,immunosuppressive and/or immunomodulatory agents, steroids,non-steroidal anti-inflammatory agents, antihistamines, analgesics, andsuitable mixtures thereof.
 4. A method of inhibiting dihydrooratedehydrogenase (DHODH) activity in a mammal comprising administering tothe mammal a compound of claim 1, wherein the compound inhibits DHODHactivity in the mammal.
 5. A compound selected from2-(6-(3-Methoxyphenyl)pyridin-3-ylcarbamoyl)benzoic acid2-(3′-Ethoxy-3-fluorobiphenyl-4-ylcarbamoyl)benzoic acid2-[3-Fluoro-3′-(trifluoromethoxy)biphenyl-4-ylcarbamoyl]benzoic acid2-[2′-Fluoro-3-(trifluoromethoxy)biphenyl-4-ylcarbamoyl]benzoic acid2-(3-fluoro-3′-methoxybiphenyl-4-ylcarbamoyl)benzoic acid2-(3′-ethoxybiphenyl-4-ylcarbamoyl)benzoic acid2-[3′-(ethylthio)-2,3,5,6-tetrafluorobiphenyl-4-ylcarbamoyl]benzoic acid2-(2′-chloro-2-fluoro-5′-methoxybiphenyl-4-ylcarbamoyl)benzoic acid2-(3-fluoro-3′-propoxybiphenyl-4-ylcarbamoyl)benzoic acid2-(3′-propoxybiphenyl-4-ylcarbamoyl)benzoic acid2-[3′-(ethylthio)-2-fluorobiphenyl-4-ylcarbamoyl]benzoic acid2-(2′-chlorobiphenyl-4-ylcarbamoyl)benzoic acid2-(3′-methoxybiphenyl-4-ylcarbamoyl)benzoic acid2-[3′-(trifluoromethoxy)biphenyl-4-ylcarbamoyl]benzoic acid2-(3′-ethylbiphenyl-4-ylcarbamoyl)benzoic acid2-(3′-butoxy-2,3,5,6-tetrafluorobiphenyl-4-ylcarbamoyl)benzoic acid2-(3′-butoxy-3-fluorobiphenyl-4-ylcarbamoyl)benzoic acid2-(3′-cyclopropoxy-3-fluorobiphenyl-4-ylcarbamoyl)benzoic acid2-(3′-cyclopropoxybiphenyl-4-ylcarbamoyl)benzoic acid2-(3′-butoxybiphenyl-4-ylcarbamoyl)benzoic acid2-(3′-butoxy-2-fluorobiphenyl-4-ylcarbamoyl)benzoic acid2-[2,6-Difluoro-4-(3-propyl-1H-indol-5-yl)phenylcarbamoyl]benzoic acid2-[2-Chloro-4-(3-ethyl-1H-indol-5-yl)-6-fluorophenylcarbamoyl]benzoicacid and pharmaceutically acceptable salts thereof.
 6. A pharmaceuticalcomposition, comprising a compound of claim 5 and a pharmaceuticallyacceptable carrier.
 7. The pharmaceutical composition of claim 6,further comprising one or more additional therapeutic agents selectedfrom the group consisting of anti-inflammatory agents, immunosuppressiveand/or immunomodulatory agents, steroids, non-steroidalanti-inflammatory agents, antihistamines, analgesics, and suitablemixtures thereof.
 8. A method of inhibiting DHODH activity in a mammalcomprising administering to the mammal a compound of claim 5, whereinthe compound inhibits DHODH activity in the mammal.